rs1332573754

Variant names:

• chrX-136207911-G-A
• rs1332573754
• NM_001159702.3:c.451G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001159702.3(FHL1):​c.451G>A​(p.Val151Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V151A) 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 NM_001159702.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.19
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• X-linked myopathy with postural muscle atrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• myopathy, reducing body, X-linked, early-onset, severe

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• reducing body myopathy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Emery-Dreifuss muscular dystrophy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked scapuloperoneal muscular dystrophy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001159702.3
• 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	c.451G>A	p.Val151Met	missense_variant	Exon 5 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.499G>A	p.Val167Met	missense_variant	Exon 4 of 6	ENST00000370683.6	NP_001153171.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183408 AF XY: 0.0000147

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30205

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842086

Other (OTH) AF: 0.00 AC: 0 AN: 46095

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

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

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	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
PhyloP100		3.2
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
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

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