chrX-136207918-G-T

Variant names:

• chrX-136207918-G-T
• NM_001159702.3:c.458G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001159699.2(FHL1):​c.506G>T​(p.Cys169Phe) 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant X-136207918-G-T is Pathogenic according to our data. Variant chrX-136207918-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2578367.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.458G>T	p.Cys153Phe	missense_variant	Exon 5 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.506G>T	p.Cys169Phe	missense_variant	Exon 4 of 6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.458G>T	p.Cys153Phe	missense_variant	Exon 5 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.506G>T	p.Cys169Phe	missense_variant	Exon 4 of 6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Myopathy, reducing body, X-linked, early-onset, severe Pathogenic:1

-

Institute of Human Genetics, University of Wuerzburg

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	.;D;.;.;D;D;.;D;.;D;.;.;D;.;D;.;.;D;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;.;D;D;D;.;.;.;D;.;D;D;D;.;D;D;D;D;.
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.95	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	4.3	H;H;H;H;.;.;H;.;H;.;H;H;.;.;H;.;.;.;.;H
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-11	.;D;D;.;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	.;D;D;.;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Uncertain	0.0020	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		0.95
MutPred		0.73		Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);.;.;.;Gain of methylation at K157 (P = 0.1427);Gain of methylation at K157 (P = 0.1427);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		4.8
Varity_R		1.0

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-135290077;