rs150911744

chrX-136207142-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001159702.3(FHL1):c.283C>T(p.Arg95Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,208,800 control chromosomes in the GnomAD database, including 1 homozygotes. There are 151 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R95Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., 15 hem., cov: 23)
  • Exomes 𝑓: 0.00033 (1 hom. 136 hem.)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.614

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001159702.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010588586).
• BP6: Variant X-136207142-C-T is Benign according to our data. Variant chrX-136207142-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 239007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000326 (357/1096567) while in subpopulation AMR AF= 0.000256 (9/35168). AF 95% confidence interval is 0.000133. There are 1 homozygotes in gnomad4_exome. There are 136 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3	c.283C>T	p.Arg95Trp	missense_variant	4/8	ENST00000394155.8
FHL1	NM_001159699.2	c.331C>T	p.Arg111Trp	missense_variant	3/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.283C>T	p.Arg95Trp	missense_variant	4/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.331C>T	p.Arg111Trp	missense_variant	3/6	1	NM_001159699.2	P1

Frequencies

GnomAD3 genomes AF: 0.000285 AC: 32 AN: 112233 Hom.: 0 Cov.: 23 AF XY: 0.000436 AC XY: 15 AN XY: 34393

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0106

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000681 AC: 124 AN: 182189 Hom.: 1 AF XY: 0.000628 AC XY: 42 AN XY: 66861

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.000106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000148

Gnomad OTH exome AF: 0.00156

GnomAD4 exome AF: 0.000326 AC: 357 AN: 1096567 Hom.: 1 Cov.: 31 AF XY: 0.000376 AC XY: 136 AN XY: 362023

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000256

Gnomad4 ASJ exome AF: 0.0138

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.0000555

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000499

Gnomad4 OTH exome AF: 0.000761

GnomAD4 genome AF: 0.000285 AC: 32 AN: 112233 Hom.: 0 Cov.: 23 AF XY: 0.000436 AC XY: 15 AN XY: 34393

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0106

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000565

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00133 Hom.: 27

Bravo AF: 0.000348

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.000478 AC: 58

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 01, 2022	Variant summary: FHL1 c.283C>T (p.Arg95Trp) results in a non-conservative amino acid change located in the Zinc finger, LIM-type domain (IPR001781) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 182189 control chromosomes with 1 homozygote and 42 hemizygotes (gnomAD). The variant occurred predominantly at a frequency of 0.013 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 35 hemizygotes. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 34 fold of the estimated maximal expected allele frequency for a pathogenic variant in FHL1 causing Emery-Dreifuss Muscular Dystrophy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.283C>T has been reported in the literature in individuals affected with peripheral neuropathy and muscle weakness (Selcen_ 2011), pediatric cardiomyopathy (Kuhnisch_2019) and hypoparathyroidism (Pillar_2017). These reports do not provide unequivocal conclusions about association of the variant with Emery-Dreifuss Muscular Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: two classified the variant as likely benign and one as benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2018	- -

X-linked myopathy with postural muscle atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

FHL1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2020

This variant is associated with the following publications: (PMID: 22094483, 28444561) -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 18, 2020

This alteration is classified as 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	0.24
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Uncertain	24
Dann	Pathogenic	1.0
FATHMM_MKL	Benign	0.14	N
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.011	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	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.4	M;M;M;.;M;.;.;.;.;M;.;M;.;M;M;.;.;.;M;.;.;.;.;.;M
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
Sift4G	Uncertain	0.014	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		0.27
MVP		0.99
MPC		1.1
ClinPred		0.11	T
GERP RS		5.0
Varity_R		0.44

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: rs150911744; hg19: chrX-135289301;