rs267606813

chrX-136207829-C-AchrX-136207829-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001159702.3(FHL1):c.369C>A(p.His123Gln) 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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H123L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.177

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 16 ACMG points.

• PS1: Transcript NM_001159702.3 (FHL1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 11562
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 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-136207828-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 537353.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-136207829-C-A is Pathogenic according to our data. Variant chrX-136207829-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1392309.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3	c.369C>A	p.His123Gln	missense_variant	5/8	ENST00000394155.8
FHL1	NM_001159699.2	c.417C>A	p.His139Gln	missense_variant	4/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.369C>A	p.His123Gln	missense_variant	5/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.417C>A	p.His139Gln	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:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked myopathy with postural muscle atrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His123 amino acid residue in FHL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22094483, 31204143; 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been observed in individual(s) with reducing body myopathy (PMID: 19181672). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with glutamine at codon 123 of the FHL1 protein (p.His123Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Uncertain	24
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Pathogenic	0.81	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;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.2	H;H;H;.;H;.;.;.;.;H;.;H;.;H;H;.;.;.;H;.;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.
Vest4		0.96
MutPred		0.96		Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);.;.;.;Gain of catalytic residue at H123 (P = 0.0191);Gain of catalytic residue at H123 (P = 0.0191);
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		2.4
Varity_R		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-135289988;