chrX-136209928-G-C

Variant names:

• chrX-136209928-G-C
• rs56391414
• NM_001159702.3:c.946G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001159702.3(FHL1):​c.946G>C​(p.Ala316Pro) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A316S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.60
• 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 2 ACMG points.

• 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.946G>C	p.Ala316Pro	missense_variant	Exon 8 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.794G>C	p.Cys265Ser	missense_variant	Exon 6 of 6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.946G>C	p.Ala316Pro	missense_variant	Exon 8 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.794G>C	p.Cys265Ser	missense_variant	Exon 6 of 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

May 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

X-linked scapuloperoneal muscular dystrophy Uncertain:1

Dec 13, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
PhyloP100		9.6
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
Mutation Taster		=3/97	disease causing

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: rs56391414; hg19: chrX-135292087;