rs1556638703

Positions:

• chrX-136206551-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001159702.3(FHL1):​c.119G>A​(p.Cys40Tyr) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C40R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.98

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3	c.119G>A	p.Cys40Tyr	missense_variant	3/8	ENST00000394155.8
FHL1	NM_001159699.2	c.167G>A	p.Cys56Tyr	missense_variant	2/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.119G>A	p.Cys40Tyr	missense_variant	3/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.167G>A	p.Cys56Tyr	missense_variant	2/6	1	NM_001159699.2	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 19, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 546307). This variant has not been reported in the literature in individuals affected with FHL1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 40 of the FHL1 protein (p.Cys40Tyr). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2018

The C40Y variant of uncertain significance in the FHL1 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The C40Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	29
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.97	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;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.4	H;H;H;.;H;.;.;.;.;H;.;.;H;.;.;H;H;.;.;.;H;.;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	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;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.
Vest4		0.95
MutPred		0.76		Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);.;.;.;Gain of ubiquitination at K45 (P = 0.1989);Gain of ubiquitination at K45 (P = 0.1989);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97

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: rs1556638703; hg19: chrX-135288710;