rs1332573754

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001159699.2(FHL1):c.499G>A(p.Val167Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 3 hem. )

Failed GnomAD Quality Control

Consequence

FHL1
NM_001159699.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.19

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3 link	c.451G>A	p.Val151Met	missense_variant	Exon 5 of 8	ENST00000394155.8	NP_001153174.1	Q13642-2
FHL1	NM_001159699.2 link	c.499G>A	p.Val167Met	missense_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.451G>A	p.Val151Met	missense_variant	Exon 5 of 8	5	NM_001159702.3	ENSP00000377710.2		Q13642-2
FHL1	ENST00000370683.6 link	c.499G>A	p.Val167Met	missense_variant	Exon 4 of 6	1	NM_001159699.2	ENSP00000359717.1		Q13642-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183408

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000273

AC:

AN:

1098190

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

363544

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked myopathy with postural muscle atrophy

Uncertain:2

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 151 of the FHL1 protein (p.Val151Met). This variant is present in population databases (no rsID available, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with FHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 548468). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

.;T;.;T;.;T;T;.;T;.;T;.;.;T;.;T;.;.;T;T;.

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

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

M_CAP

Benign

0.069

MetaRNN

Uncertain

0.60

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

1.9

L;L;L;.;L;.;.;L;.;L;.;L;L;.;.;L;.;.;.;.;L

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.8

.;N;N;.;.;N;N;.;N;N;N;N;N;N;.;N;N;N;N;N;.

REVEL

Uncertain

0.48

Sift

Uncertain

0.021

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

Sift4G

Benign

0.066

T;T;T;D;T;D;T;T;T;T;T;T;T;D;T;T;T;T;T;T;T

Polyphen

0.67, 0.44

.;P;.;.;.;.;.;.;.;.;.;.;.;.;.;P;.;.;B;.;.

Vest4

0.57

MutPred

0.36

Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);.;.;.;Gain of catalytic residue at V151 (P = 0.0636);Gain of catalytic residue at V151 (P = 0.0636);

MVP

0.90

MPC

1.0

ClinPred

0.62

GERP RS

4.8

Varity_R

0.51

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