rs869025431

Positions:

• chrX-136209946-G-A
• chrX-136209946-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_001159702.3(FHL1):​c.964G>A​(p.Ala322Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. A322G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-136209946-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25534466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3	c.964G>A	p.Ala322Thr	missense_variant	8/8	ENST00000394155.8
FHL1	NM_001159699.2	c.812G>A	p.Cys271Tyr	missense_variant	6/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.964G>A	p.Ala322Thr	missense_variant	8/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.812G>A	p.Cys271Tyr	missense_variant	6/6	1	NM_001159699.2	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked myopathy with postural muscle atrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 21, 2020

This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 255 of the FHL1 protein (p.Cys255Tyr). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant has not been reported in the literature in individuals with FHL1-related disease. 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. The p.Cys255Ser amino acid residue in FHL1 has been determined to be clinically significant (PMID: 25246303, 26857240). This suggests that variants that disrupt this residue are likely to be causative of disease. 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"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;T;.;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.0	N;.;N;.
MutationTaster	Benign	0.85	D;D;D;D;D;D;D;D;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.040	N;.;N;N
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;.;D;T
Sift4G	Pathogenic	0.0	.;D;.;D
Polyphen		0.020	B;B;B;B
Vest4		0.15
MutPred		0.12		Gain of glycosylation at A322 (P = 0.0072);.;Gain of glycosylation at A322 (P = 0.0072);.;
MVP		1.0
MPC		1.2
ClinPred		0.71	D
GERP RS		4.7
Varity_R		0.35

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: rs869025431; hg19: chrX-135292105;