rs122458142

Variant names:

• chrX-136207827-C-T
• rs122458142
• NM_001159702.3:c.367C>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.415C>T​(p.His139Tyr) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.91

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, 0.992
• PP5: Variant X-136207827-C-T is Pathogenic according to our data. Variant chrX-136207827-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11550.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-136207827-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.367C>T	p.His123Tyr	missense_variant	Exon 5 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.415C>T	p.His139Tyr	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.367C>T	p.His123Tyr	missense_variant	Exon 5 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.415C>T	p.His139Tyr	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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Feb 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;.;D;.;D;D;D;.;.;D;.;D;.;.;D;.;D;D;.;.;.;D;D;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	.;D;.;D;D;D;D;D;D;.;.;.;D;.;D;D;D;D;.;.;D;D;D;D;.
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	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	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;H;.;H;.;.;.;.;H;.;H;.;H;H;.;.;.;H;.;.;.;.;.;H
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.8	.;D;D;.;.;D;D;.;.;.;D;D;D;D;D;D;.;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;D;.;.;D;D;.;.;.;D;D;D;D;D;D;.;D;D;.;D;D;D;D;.
Sift4G	Pathogenic	0.0010	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		0.97
MutPred		0.95		Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);.;.;.;Loss of methylation at K124 (P = 0.07);Loss of methylation at K124 (P = 0.07);
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		4.7
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

LitVar

Other links and lift over

dbSNP: rs122458142; hg19: chrX-135289986;