chrX-136209920-C-A

Variant names:

• chrX-136209920-C-A
• rs141231353
• NM_001159702.3:c.938C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001159702.3(FHL1):​c.938C>A​(p.Thr313Lys) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T313M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.332
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• X-linked myopathy with postural muscle atrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• myopathy, reducing body, X-linked, early-onset, severe

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• reducing body myopathy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Emery-Dreifuss muscular dystrophy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked scapuloperoneal muscular dystrophy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.938C>A	p.Thr313Lys	missense_variant	Exon 8 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.786C>A	p.His262Gln	missense_variant	Exon 6 of 6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.938C>A	p.Thr313Lys	missense_variant	Exon 8 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.786C>A	p.His262Gln	missense_variant	Exon 6 of 6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked myopathy with postural muscle atrophy Uncertain:1

Sep 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine with glutamine at codon 246 of the FHL1 protein (p.His246Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FHL1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	.;.;.;.;.;.;.;.;D;.
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.98	.;.;.;.;.;D;D;D;D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.78	T
PhyloP100		0.33
PROVEAN	Pathogenic	-7.5	.;D;.;D;D;D;D;D;D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	.;D;.;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Vest4		0.93
MutPred		0.82		.;.;.;.;.;.;Gain of catalytic residue at H275 (P = 0.0905);.;.;.;
MVP		0.88
ClinPred		0.60	D
GERP RS		4.6
Varity_R		0.40
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs141231353; hg19: chrX-135292079;