rs746834335

Positions:

• chrX-136207050-C-A
• chrX-136207050-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001159699.2(FHL1):​c.239C>A​(p.Thr80Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000082 in 1,097,981 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000082 (0 hom. 3 hem.)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.129

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17033195).
• 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.191C>A	p.Thr64Asn	missense_variant	4/8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.239C>A	p.Thr80Asn	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.191C>A	p.Thr64Asn	missense_variant	4/8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.239C>A	p.Thr80Asn	missense_variant	3/6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183137 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67645

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1097981 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 3 AN XY: 363407

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000950

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 24

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Uruguay Faciocardiomusculoskeletal syndrome;C2678055:X-linked myopathy with postural muscle atrophy;C2678061:X-linked scapuloperoneal muscular dystrophy;C4225159:Myopathy, reducing body, X-linked, childhood-onset;C4225423:Myopathy, reducing body, X-linked, early-onset, severe Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 28, 2021

- -

X-linked myopathy with postural muscle atrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2024

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 64 of the FHL1 protein (p.Thr64Asn). This variant is present in population databases (no rsID available, gnomAD 0.001%). 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: 838581). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

Dec 08, 2020

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.21	.;T;.;T;.;T;T;T;.;.;T;T;.;T;T;.;.;T;.;T;T;.;.;.;T;T;.
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.77	.;T;.;T;T;T;T;T;T;.;T;.;.;T;T;.;T;T;T;T;.;.;T;T;T;T;.
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.69	N;N;N;.;N;.;.;.;.;N;.;.;N;.;.;N;N;.;.;.;N;.;.;.;.;.;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.13	.;N;N;.;.;N;N;.;.;.;.;N;N;.;N;N;N;N;.;N;N;.;N;N;N;N;.
REVEL	Benign	0.15
Sift	Benign	0.49	.;T;T;.;.;T;T;.;.;.;.;T;T;.;T;T;T;T;.;T;T;.;T;T;T;T;.
Sift4G	Benign	0.51	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0040, 0.0	.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;B;.;.;.;B;.;.
Vest4		0.23
MVP		0.46
MPC		0.60
ClinPred		0.028	T
GERP RS		4.0
Varity_R		0.070

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: rs746834335; hg19: chrX-135289209;