rs756434530

chrX-136207151-T-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BS1_Supporting BS2

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. 12/18 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.55

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]

ACMG classification

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, 7 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 GnomAdExome at 4 XL gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112179 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34355

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: 10 AN: 181669 Hom.: 0 AF XY: 0.0000603 AC XY: 4 AN XY: 66389

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: 44 AN: 1096082 Hom.: 0 Cov.: 31 AF XY: 0.0000249 AC XY: 9 AN XY: 361616

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: 2 AN: 112179 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34355

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.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked myopathy with postural muscle atrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	15
Dann	Uncertain	0.97
FATHMM_MKL	Benign	0.21	N
M_CAP	Uncertain	0.13	D
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	T
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	T
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	T
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

Other links and lift over

dbSNP: rs756434530; hg19: chrX-135289310;