rs1060502840

Positions:

• chrX-136206491-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001159702.3(FHL1):​c.60del​(p.Gln21LysfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V20V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: FHL1 NM_001159702.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.36

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 56 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-136206491-TG-T is Pathogenic according to our data. Variant chrX-136206491-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 410317.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.60del	p.Gln21LysfsTer9	frameshift_variant	3/8	ENST00000394155.8
FHL1	NM_001159699.2	c.108del	p.Gln37LysfsTer9	frameshift_variant	2/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.60del	p.Gln21LysfsTer9	frameshift_variant	3/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.108del	p.Gln37LysfsTer9	frameshift_variant	2/6	1	NM_001159699.2	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

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

Mar 06, 2020

This sequence change creates a premature translational stop signal (p.Gln21Lysfs*9) in the FHL1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in FHL1 are known to be pathogenic (PMID: 18179888, 19687455, 19716112, 22523091, 24114807). This variant has not been reported in the literature in individuals with FHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 410317). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

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: rs1060502840; hg19: chrX-135288650;