chrX-136209862-TC-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001159702.3(FHL1):c.889-3delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000656 in 1,162,380 control chromosomes in the GnomAD database, including 1 homozygotes. There are 168 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., 33 hem., cov: 20)

Exomes 𝑓: 0.00057 ( 1 hom. 135 hem. )

Consequence

FHL1
NM_001159702.3 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.111

Publications

1 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 -16 ACMG points.

BP6

Variant X-136209862-TC-T is Benign according to our data. Variant chrX-136209862-TC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00147 (161/109191) while in subpopulation AFR AF = 0.00432 (130/30082). AF 95% confidence interval is 0.00372. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 33 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3 link	c.889-3delC		splice_region_variant, intron_variant	Intron 7 of 7	ENST00000394155.8	NP_001153174.1	Q13642-2
FHL1	NM_001159699.2 link	c.737-3delC		splice_region_variant, intron_variant	Intron 5 of 5	ENST00000370683.6	NP_001153171.1	Q13642-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8 link	c.889-8delC		splice_region_variant, intron_variant	Intron 7 of 7	5	NM_001159702.3	ENSP00000377710.2		Q13642-2
FHL1	ENST00000370683.6 link	c.737-8delC		splice_region_variant, intron_variant	Intron 5 of 5	1	NM_001159699.2	ENSP00000359717.1		Q13642-5

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

160

AN:

109147

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00430

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000879

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000286

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000178

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000344

Gnomad OTH

AF:

0.00136

GnomAD2 exomes

AF:

0.00130

AC:

219

AN:

168269

AF XY:

0.000498

show subpopulations

Gnomad AFR exome

AF:

0.00484

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.000573

Gnomad EAS exome

AF:

0.00113

Gnomad FIN exome

AF:

0.000401

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.00214

GnomAD4 exome

AF:

0.000572

AC:

602

AN:

1053189

Hom.:

Cov.:

AF XY:

0.000398

AC XY:

135

AN XY:

339267

show subpopulations

African (AFR)

AF:

0.00526

AC:

135

AN:

25650

American (AMR)

AF:

0.00111

AC:

AN:

33342

Ashkenazi Jewish (ASJ)

AF:

0.000161

AC:

AN:

18665

East Asian (EAS)

AF:

0.000208

AC:

AN:

28848

South Asian (SAS)

AF:

0.000486

AC:

AN:

51398

European-Finnish (FIN)

AF:

0.000391

AC:

AN:

38367

Middle Eastern (MID)

AF:

0.00113

AC:

AN:

3553

European-Non Finnish (NFE)

AF:

0.000430

AC:

348

AN:

809051

Other (OTH)

AF:

0.000654

AC:

AN:

44315

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00147

AC:

161

AN:

109191

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

AN XY:

31721

show subpopulations

African (AFR)

AF:

0.00432

AC:

130

AN:

30082

American (AMR)

AF:

0.000878

AC:

AN:

10249

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2624

East Asian (EAS)

AF:

0.000287

AC:

AN:

3480

South Asian (SAS)

AF:

0.00

AC:

AN:

2462

European-Finnish (FIN)

AF:

0.000178

AC:

AN:

5607

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.000344

AC:

AN:

52312

Other (OTH)

AF:

0.00134

AC:

AN:

1488

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000784

Hom.:

Bravo

AF:

0.00179

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 13, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Oct 25, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked myopathy with postural muscle atrophy

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 28, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

PhyloP100

-0.11

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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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