X-136207034-C-T

Position:

• chrX-136207034-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001159702.3(FHL1):​c.175C>T​(p.Arg59Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,097,713 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 3 hem.)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.175C>T	p.Arg59Cys	missense_variant	4/8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.223C>T	p.Arg75Cys	missense_variant	3/6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.175C>T	p.Arg59Cys	missense_variant	4/8	5	NM_001159702.3	ENSP00000377710
FHL1	ENST00000370683.6	c.223C>T	p.Arg75Cys	missense_variant	3/6	1	NM_001159699.2	ENSP00000359717	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1097713 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 3 AN XY: 363309

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked myopathy with postural muscle atrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 59 of the FHL1 protein (p.Arg59Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 537352). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Aug 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	.;D;.;T;.;D;D;T;.;.;T;D;.;T;D;.;.;D;.;D;D;.;.;.;D;D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;.;D;D;D;D;D;D;.;T;.;.;D;D;.;D;D;D;D;.;.;D;D;D;D;.
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.91	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;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	2.9	M;M;M;.;M;.;.;.;.;M;.;.;M;.;.;M;M;.;.;.;M;.;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.6	.;D;D;.;.;D;D;.;.;.;.;D;D;.;D;D;D;D;.;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0060	.;D;D;.;.;D;D;.;.;.;.;D;D;.;D;D;D;D;.;D;D;.;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;T;D;D;T;T;T;D;T;D;D;T;D;D;D;D;D;T;D;T;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.
Vest4		0.84
MutPred		0.68		Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);.;.;.;Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);
MVP		0.99
MPC		0.84
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.64

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: rs1343871742; hg19: chrX-135289193;