rs122459146

Positions:

• chrX-136207909-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001159702.3(FHL1):​c.449G>A​(p.Cys150Tyr) 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 pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C150R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001159702.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-136207908-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 689729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-136207909-G-A is Pathogenic according to our data. Variant chrX-136207909-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11554.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-136207909-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3	c.449G>A	p.Cys150Tyr	missense_variant	5/8	ENST00000394155.8
FHL1	NM_001159699.2	c.497G>A	p.Cys166Tyr	missense_variant	4/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.449G>A	p.Cys150Tyr	missense_variant	5/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.497G>A	p.Cys166Tyr	missense_variant	4/6	1	NM_001159699.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy, reducing body, X-linked, early-onset, severe Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 27, 2009

- -

X-linked myopathy with postural muscle atrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 09, 2021

This sequence change replaces cysteine with tyrosine at codon 150 of the FHL1 protein (p.Cys150Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys150 amino acid residue in FHL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with myopathy (PMID: 19171836, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11554). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.83
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;.;T;.;D;D;.;D;.;D;.;.;D;.;D;.;.;D;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;.;D;D;D;D;.;.;.;D;.;D;D;D;.;D;D;D;D;.
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.5	H;H;H;.;H;.;.;H;.;H;.;H;H;.;.;H;.;.;.;.;H
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-11	.;D;D;.;.;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;D;D;.;.;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D;.;.
Vest4		0.95
MutPred		0.90		Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);.;.;.;Loss of catalytic residue at T152 (P = 0.1009);Loss of catalytic residue at T152 (P = 0.1009);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.99

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: rs122459146; hg19: chrX-135290068;