rs122458144

Positions:

• chrX-136207917-T-A
• chrX-136207917-T-C
• chrX-136207917-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001159699.2(FHL1):​c.505T>A​(p.Cys169Ser) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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]

FHL1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant X-136207917-T-A is Pathogenic according to our data. Variant chrX-136207917-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1404846.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.457T>A	p.Cys153Ser	missense_variant	5/8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.505T>A	p.Cys169Ser	missense_variant	4/6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.457T>A	p.Cys153Ser	missense_variant	5/8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.505T>A	p.Cys169Ser	missense_variant	4/6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	.;D;.;.;D;D;.;D;.;D;.;.;D;.;D;.;.;D;D;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	.;D;.;D;D;D;.;.;.;D;.;D;D;D;.;D;D;D;D;.
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;H;H;H;.;.;H;.;H;.;H;H;.;.;H;.;.;.;.;H
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-9.7	.;D;D;.;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D;D;.;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Uncertain	0.020	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		0.95
MutPred		0.75		Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);.;.;.;Loss of stability (P = 0.0608);Loss of stability (P = 0.0608);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		4.8
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-135290076;