rs151315725

Positions:

chrX-136210005-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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

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 links:

FHL1 (HGNC:):

FHL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 id is 239013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136210005-G-A is described in Lovd as [Benign]. Variant chrX-136210005-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHL1	NM_001159699.2 linkuse as main transcript	c.871G>A	p.Asp291Asn	missense_variant	6/6	ENST00000370683.6	NP_001153171.1	Q13642-5
FHL1	NM_001159702.3 linkuse as main transcript	c.*51G>A		3_prime_UTR_variant	8/8	ENST00000394155.8	NP_001153174.1	Q13642-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000370683.6 linkuse as main transcript	c.871G>A	p.Asp291Asn	missense_variant	6/6	1	NM_001159699.2	ENSP00000359717.1		Q13642-5
FHL1	ENST00000394155.8 linkuse as main transcript	c.*51G>A		3_prime_UTR_variant	8/8	5	NM_001159702.3	ENSP00000377710.2		Q13642-2

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1274

AN:

110492

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

329

AN XY:

32716

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

GnomAD3 exomes

AF:

0.0109

AC:

1994

AN:

183528

Hom.:

AF XY:

0.0113

AC XY:

765

AN XY:

67958

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 SAS exome

AF:

0.00535

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

Gnomad4 AFR exome

AF:

0.00208

Gnomad4 AMR exome

AF:

0.00648

Gnomad4 ASJ exome

AF:

0.00134

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00624

Gnomad4 FIN exome

AF:

0.00570

Gnomad4 NFE exome

AF:

0.0201

Gnomad4 OTH exome

AF:

0.0125

GnomAD4 genome

AF:

0.0115

AC:

1272

AN:

110547

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

328

AN XY:

32781

show subpopulations

Gnomad4 AFR

AF:

0.00296

Gnomad4 AMR

AF:

0.0100

Gnomad4 ASJ

AF:

0.00190

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00702

Gnomad4 FIN

AF:

0.00362

Gnomad4 NFE

AF:

0.0194

Gnomad4 OTH

AF:

0.00535

Alfa

AF:

0.0164

Hom.:

719

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2021	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. -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 24, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

X-linked myopathy with postural muscle atrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Familial hemophagocytic lymphohistiocytosis type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 19, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2019

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over