rs149670651

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001159699.2(FHL1):c.489C>T(p.Asp163Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,211,068 control chromosomes in the GnomAD database, including 8 homozygotes. There are 995 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., 57 hem., cov: 23)

Exomes 𝑓: 0.0027 ( 8 hom. 938 hem. )

Consequence

FHL1
NM_001159699.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.351

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant X-136207901-C-T is Benign according to our data. Variant chrX-136207901-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 239009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136207901-C-T is described in Lovd as [Benign]. Variant chrX-136207901-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.351 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00156 (176/112899) while in subpopulation NFE AF= 0.00277 (148/53343). AF 95% confidence interval is 0.00241. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 57 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3 link	c.441C>T	p.Asp147Asp	synonymous_variant	Exon 5 of 8	ENST00000394155.8	NP_001153174.1	Q13642-2
FHL1	NM_001159699.2 link	c.489C>T	p.Asp163Asp	synonymous_variant	Exon 4 of 6	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.441C>T	p.Asp147Asp	synonymous_variant	Exon 5 of 8	5	NM_001159702.3	ENSP00000377710.2		Q13642-2
FHL1	ENST00000370683.6 link	c.489C>T	p.Asp163Asp	synonymous_variant	Exon 4 of 6	1	NM_001159699.2	ENSP00000359717.1		Q13642-5

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

176

AN:

112846

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

AN XY:

34986

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000465

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000733

Gnomad FIN

AF:

0.00177

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00277

Gnomad OTH

AF:

0.000655

GnomAD3 exomes

AF:

0.00165

AC:

303

AN:

183432

Hom.:

AF XY:

0.00183

AC XY:

124

AN XY:

67870

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.000401

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000943

Gnomad FIN exome

AF:

0.00375

Gnomad NFE exome

AF:

0.00245

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00267

AC:

2936

AN:

1098169

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

938

AN XY:

363527

show subpopulations

Gnomad4 AFR exome

AF:

0.000303

Gnomad4 AMR exome

AF:

0.000653

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00118

Gnomad4 FIN exome

AF:

0.00336

Gnomad4 NFE exome

AF:

0.00311

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00156

AC:

176

AN:

112899

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

AN XY:

35049

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000464

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000735

Gnomad4 FIN

AF:

0.00177

Gnomad4 NFE

AF:

0.00277

Gnomad4 OTH

AF:

0.000647

Alfa

AF:

0.00200

Hom.:

Bravo

AF:

0.00131

EpiCase

AF:

0.00207

EpiControl

AF:

0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2015

Eurofins Ntd Llc (ga)

Significance: 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

- -

Apr 21, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

May 20, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22523091, 19377476) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

X-linked myopathy with postural muscle atrophy

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hemophagocytic lymphohistiocytosis type 1

Benign:1

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 18, 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

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.50

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