X-136209928-G-C

Position:

• chrX-136209928-G-C

Variant summary

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

The NM_001159699.2(FHL1):​c.794G>C​(p.Cys265Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.60

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.946G>C	p.Ala316Pro	missense_variant	8/8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.794G>C	p.Cys265Ser	missense_variant	6/6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.946G>C	p.Ala316Pro	missense_variant	8/8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.794G>C	p.Cys265Ser	missense_variant	6/6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

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:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2018

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals with FHL1-related disease. This sequence change replaces cysteine with serine at codon 249 of the FHL1 protein (p.Cys249Ser). The cysteine residue is moderately conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). -

X-linked scapuloperoneal muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 13, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;T;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T;T;.;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	0.0	N;.;N;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.020	N;.;N;N
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.051	.;T;.;D
Polyphen		0.98	D;D;D;D
Vest4		0.24
MutPred		0.14		Gain of glycosylation at A316 (P = 0.0299);.;Gain of glycosylation at A316 (P = 0.0299);.;
MVP		0.97
MPC		1.5
ClinPred		0.88	D
GERP RS		5.6
Varity_R		0.59

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: rs56391414; hg19: chrX-135292087;