rs1332573754

Positions:

• chrX-136207911-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The ENST00000370683.6(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V167A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 3 hem.)
  • Failed GnomAD Quality Control
• Consequence: FHL1 ENST00000370683.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.19

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000370683.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.451G>A	p.Val151Met	missense_variant	5/8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.499G>A	p.Val167Met	missense_variant	4/6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.451G>A	p.Val151Met	missense_variant	5/8	5	NM_001159702.3	ENSP00000377710
FHL1	ENST00000370683.6	c.499G>A	p.Val167Met	missense_variant	4/6	1	NM_001159699.2	ENSP00000359717	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183408 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67854

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: 3 AN: 1098190 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 3 AN XY: 363544

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.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked myopathy with postural muscle atrophy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2020	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 548468). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 151 of the FHL1 protein (p.Val151Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;T;.;T;.;T;T;.;T;.;T;.;.;T;.;T;.;.;T;T;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	.;D;.;D;D;D;D;.;.;.;D;.;D;D;D;.;D;D;D;D;.
M_CAP	Benign	0.069	D
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	D
MutationAssessor	Benign	1.9	L;L;L;.;L;.;.;L;.;L;.;L;L;.;.;L;.;.;.;.;L
MutationTaster	Benign	0.80	D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.68	T
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	D
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

Other links and lift over

dbSNP: rs1332573754; hg19: chrX-135290070; COSMIC: COSV61780993; COSMIC: COSV61780993;