rs145445372

chrX-136207910-C-GchrX-136207910-C-T

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.450C>G(p.Cys150Trp) 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 Likely 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: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0320

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, 0.984
• PP5: Variant X-136207910-C-G is Pathogenic according to our data. Variant chrX-136207910-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 943902.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.450C>G	p.Cys150Trp	missense_variant	5/8	ENST00000394155.8
FHL1	NM_001159699.2	c.498C>G	p.Cys166Trp	missense_variant	4/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.450C>G	p.Cys150Trp	missense_variant	5/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.498C>G	p.Cys166Trp	missense_variant	4/6	1	NM_001159699.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked myopathy with postural muscle atrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys150 amino acid residue in FHL1. Other variant(s) that disrupt this residue have been observed in individuals with FHL1-related conditions (PMID: 19171836, 20571991, 23169582, 25191266), which suggests that this may be a clinically significant amino acid residue. 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: 943902). This missense change has been observed in individual(s) with X-linked dominant FHL1-related conditions (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 150 of the FHL1 protein (p.Cys150Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
Cadd	Uncertain	23
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	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	0.84	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		0.96
MutPred		0.86		Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);.;.;.;Loss of catalytic residue at T152 (P = 0.0915);Loss of catalytic residue at T152 (P = 0.0915);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		0.54
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: rs145445372; hg19: chrX-135290069;