rs122458143

Positions:

• chrX-136207855-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001159702.3(FHL1):​c.395G>T​(p.Cys132Phe) 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 (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain LIM zinc-binding 2 (size 52) in uniprot entity FHL1_HUMAN there are 24 pathogenic changes around while only 1 benign (96%) in NM_001159702.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-136207855-G-T is Pathogenic according to our data. Variant chrX-136207855-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 11551.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-136207855-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3	c.395G>T	p.Cys132Phe	missense_variant	5/8	ENST00000394155.8
FHL1	NM_001159699.2	c.443G>T	p.Cys148Phe	missense_variant	4/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.395G>T	p.Cys132Phe	missense_variant	5/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.443G>T	p.Cys148Phe	missense_variant	4/6	1	NM_001159699.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2008

- -

Centronuclear myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Mar 01, 2024

PS1+PM1+PM2+PP3+PP4+PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.83
CADD	Pathogenic	28
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.91	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
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	4.6	H;H;H;.;H;.;.;.;.;H;.;H;.;H;H;.;.;.;H;.;.;.;.;H
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.76	T
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
Polyphen		1.0, 1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D;.;.
Vest4		0.96
MutPred		0.88		Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);.;.;.;Gain of ubiquitination at K133 (P = 0.1897);Gain of ubiquitination at K133 (P = 0.1897);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		4.7
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

LitVar

Other links and lift over

dbSNP: rs122458143; hg19: chrX-135290014;