rs756434530

Positions:

chrX-136207151-T-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBS1_SupportingBS2

The NM_001159702.3(FHL1):c.292T>A(p.Ser98Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000381 in 1,208,261 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S98P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000040 ( 0 hom. 9 hem. )

Consequence

FHL1
NM_001159702.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.55

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 Likely_benign. Variant got -5 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, 8 uncertain in NM_001159702.3

BP4

Computational evidence support a benign effect (MetaRNN=0.1392864).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000401 (44/1096082) while in subpopulation AMR AF= 0.000142 (5/35137). AF 95% confidence interval is 0.0000553. There are 0 homozygotes in gnomad4_exome. There are 9 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3 linkuse as main transcript	c.292T>A	p.Ser98Thr	missense_variant	4/8	ENST00000394155.8
FHL1	NM_001159699.2 linkuse as main transcript	c.340T>A	p.Ser114Thr	missense_variant	3/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8 linkuse as main transcript	c.292T>A	p.Ser98Thr	missense_variant	4/8	5	NM_001159702.3		Q13642-2
FHL1	ENST00000370683.6 linkuse as main transcript	c.340T>A	p.Ser114Thr	missense_variant	3/6	1	NM_001159699.2	P1	Q13642-5

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112179

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34355

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000550

AC:

AN:

181669

Hom.:

AF XY:

0.0000603

AC XY:

AN XY:

66389

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000125

Gnomad NFE exome

AF:

0.0000371

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000401

AC:

AN:

1096082

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

361616

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000988

Gnomad4 NFE exome

AF:

0.0000357

Gnomad4 OTH exome

AF:

0.0000870

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112179

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34355

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked myopathy with postural muscle atrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 15, 2022

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 98 of the FHL1 protein (p.Ser98Thr). This variant is present in population databases (rs756434530, gnomAD 0.02%). 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: 222634). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jun 30, 2015

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2022

The p.S98T variant (also known as c.292T>A), located in coding exon 2 of the FHL1 gene, results from a T to A substitution at nucleotide position 292. The serine at codon 98 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.30

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

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.76

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

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.14

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

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.27

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

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.9

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

REVEL

Benign

0.20

Sift

Uncertain

0.026

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

Sift4G

Uncertain

0.034

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

Polyphen

0.0040, 0.0010

.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;B;.;.;.;B;.;.

Vest4

0.32

MVP

0.87

MPC

0.47

ClinPred

0.043

GERP RS

3.4

Varity_R

0.23

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