chrX-136210005-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001159699.2(FHL1):c.871G>A(p.Asp291Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0163 in 1,208,769 control chromosomes in the GnomAD database, including 140 homozygotes. There are 6,223 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 9 hom., 328 hem., cov: 22)

Exomes 𝑓: 0.017 ( 131 hom. 5895 hem. )

Consequence

FHL1
NM_001159699.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 6.32

Publications

9 publications found

Variant links:

Genes affected

FHL1 (HGNC:3702): (four and a half LIM domains 1) This gene encodes a member of the four-and-a-half-LIM-only protein family. Family members contain two highly conserved, tandemly arranged, zinc finger domains with four highly conserved cysteines binding a zinc atom in each zinc finger. Expression of these family members occurs in a cell- and tissue-specific mode and these proteins are involved in many cellular processes. Mutations in this gene have been found in patients with Emery-Dreifuss muscular dystrophy. Multiple alternately spliced transcript variants which encode different protein isoforms have been described.[provided by RefSeq, Nov 2009]

FHL1 Gene-Disease associations (from GenCC):

X-linked myopathy with postural muscle atrophy
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
myopathy, reducing body, X-linked, early-onset, severe
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
reducing body myopathy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked Emery-Dreifuss muscular dystrophy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked scapuloperoneal muscular dystrophy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

FHL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_001159699.2

BP4

Computational evidence support a benign effect (MetaRNN=0.0082143545).

BP6

Variant X-136210005-G-A is Benign according to our data. Variant chrX-136210005-G-A is described in ClinVar as Benign. ClinVar VariationId is 239013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0115 (1272/110547) while in subpopulation NFE AF = 0.0194 (1026/52838). AF 95% confidence interval is 0.0184. There are 9 homozygotes in GnomAd4. There are 328 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159699.2 link	c.871G>A	p.Asp291Asn	missense_variant	Exon 6 of 6	ENST00000370683.6	NP_001153171.1	Q13642-5
FHL1	NM_001159702.3 link	c.*51G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000394155.8	NP_001153174.1	Q13642-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000370683.6 link	c.871G>A	p.Asp291Asn	missense_variant	Exon 6 of 6	1	NM_001159699.2	ENSP00000359717.1		Q13642-5
FHL1	ENST00000394155.8 link	c.*51G>A		3_prime_UTR_variant	Exon 8 of 8	5	NM_001159702.3	ENSP00000377710.2		Q13642-2

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1274

AN:

110492

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00300

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.00190

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00699

Gnomad FIN

AF:

0.00362

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0194

Gnomad OTH

AF:

0.00542

GnomAD2 exomes

AF:

0.0109

AC:

1994

AN:

183528

AF XY:

0.0113

show subpopulations

Gnomad AFR exome

AF:

0.00304

Gnomad AMR exome

AF:

0.00627

Gnomad ASJ exome

AF:

0.00107

Gnomad EAS exome

AF:

0.000216

Gnomad FIN exome

AF:

0.00531

Gnomad NFE exome

AF:

0.0187

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.0167

AC:

18390

AN:

1098222

Hom.:

131

Cov.:

AF XY:

0.0162

AC XY:

5895

AN XY:

363582

show subpopulations

African (AFR)

AF:

0.00208

AC:

AN:

26403

American (AMR)

AF:

0.00648

AC:

228

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00134

AC:

AN:

19386

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30202

South Asian (SAS)

AF:

0.00624

AC:

338

AN:

54145

European-Finnish (FIN)

AF:

0.00570

AC:

231

AN:

40529

Middle Eastern (MID)

AF:

0.00435

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0201

AC:

16916

AN:

842116

Other (OTH)

AF:

0.0125

AC:

577

AN:

46098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

778

1557

2335

3114

3892

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

650

1300

1950

2600

3250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0115

AC:

1272

AN:

110547

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

328

AN XY:

32781

show subpopulations

African (AFR)

AF:

0.00296

AC:

AN:

30377

American (AMR)

AF:

0.0100

AC:

104

AN:

10397

Ashkenazi Jewish (ASJ)

AF:

0.00190

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3532

South Asian (SAS)

AF:

0.00702

AC:

AN:

2565

European-Finnish (FIN)

AF:

0.00362

AC:

AN:

5805

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0194

AC:

1026

AN:

52838

Other (OTH)

AF:

0.00535

AC:

AN:

1496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

136

182

227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0154

Hom.:

723

Bravo

AF:

0.0110

TwinsUK

AF:

0.0213

AC:

ALSPAC

AF:

0.0232

AC:

ESP6500AA

AF:

0.00339

AC:

ESP6500EA

AF:

0.0186

AC:

125

ExAC

AF:

0.0112

AC:

1364

EpiCase

AF:

0.0160

EpiControl

AF:

0.0186

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Mar 04, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dec 03, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 29, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FHL1 c.*51G>A is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.011 in 183528 control chromosomes in the gnomAD database, including 17 homozygotes. The observed variant frequency is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in FHL1 causing Emery-Dreifuss Muscular Dystrophy phenotype (0.00039), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.*51G>A in individuals affected with Emery-Dreifuss Muscular Dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:5

Aug 24, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

X-linked myopathy with postural muscle atrophy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 03, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

.;.;.;.;.;D;D;D;.

MetaRNN

Benign

0.0082

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.10

PhyloP100

6.3

PROVEAN

Uncertain

-2.9

.;D;.;D;D;D;D;D;.

REVEL

Uncertain

0.43

Sift

Uncertain

0.026

.;D;.;D;D;D;D;D;.

Sift4G

Uncertain

0.056

T;T;T;T;T;T;T;T;T

Vest4

0.15

ClinPred

0.027

GERP RS

5.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over