X-136206434-T-C

Variant names:

• chrX-136206434-T-C
• NM_001159702.3:c.2T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001159702.3(FHL1):​c.2T>C​(p.Met1?) variant causes a start lost change. 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 (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: FHL1 NM_001159702.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.26

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.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 307 codons. Genomic position: 136209901. Lost 0.945 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-136206434-T-C is Pathogenic according to our data. Variant chrX-136206434-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2861396.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.2T>C	p.Met1?	start_lost	Exon 3 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.50T>C	p.Met17Thr	missense_variant	Exon 2 of 6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.2T>C	p.Met1?	start_lost	Exon 3 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.50T>C	p.Met17Thr	missense_variant	Exon 2 of 6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

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

May 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the FHL1 mRNA. There are no downstream in-frame methionine residues; therefore, it is expected to result in an absent or disrupted protein product. Loss-of-function variants in FHL1 are known to be pathogenic (PMID: 18179888, 19687455, 19716112, 22523091, 24114807). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FHL1-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T;.;T;.;T;T;T;.;.;T;T;T;.;T;T;.;.;T;.;T;T;.;.;.;T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;.;D;D;D;D;D;D;.;D;.;.;.;D;D;.;D;D;D;D;.;.;D;D;D;D;.
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.89	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;D
MetaSVM	Uncertain	0.099	D
PROVEAN	Uncertain	-3.1	.;D;D;.;.;D;D;.;.;.;.;D;.;D;.;D;D;D;D;.;D;D;.;D;D;D;D;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	.;D;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;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.
Vest4		0.79
MutPred		0.62		Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);.;.;.;Gain of catalytic residue at M1 (P = 0.0439);Gain of catalytic residue at M1 (P = 0.0439);
MVP		0.93
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.84

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-135288593; COSMIC: COSV100600644; COSMIC: COSV100600644;