rs141231353

chrX-136209920-C-AchrX-136209920-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001159702.3(FHL1):c.938C>A(p.Thr313Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. T313M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.332

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 5 uncertain in NM_001159702.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3	c.938C>A	p.Thr313Lys	missense_variant	8/8	ENST00000394155.8
FHL1	NM_001159699.2	c.786C>A	p.His262Gln	missense_variant	6/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.938C>A	p.Thr313Lys	missense_variant	8/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.786C>A	p.His262Gln	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

Sep 13, 2017

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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FHL1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with glutamine at codon 246 of the FHL1 protein (p.His246Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	26
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;N;N;N
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Vest4		0.93
MutPred		0.82		.;.;.;.;.;.;Gain of catalytic residue at H275 (P = 0.0905);.;.;.;
MVP		0.88
ClinPred		0.60	D
GERP RS		4.6

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: rs141231353; hg19: chrX-135292079;