X-136206434-T-C

Variant summary

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

• PVS1: Start lost variant, no new inframe start found.
• 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/exons	MANE	UniProt
FHL1	NM_001159702.3	c.2T>C	p.Met1?	start_lost	3/8	ENST00000394155.8
FHL1	NM_001159699.2	c.50T>C	p.Met17Thr	missense_variant	2/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.2T>C	p.Met1?	start_lost	3/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.50T>C	p.Met17Thr	missense_variant	2/6	1	NM_001159699.2	P1

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 01, 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 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 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). -

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
FATHMM_MKL	Pathogenic	0.99	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
MutationTaster	Benign	1.0	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;