rs754308516

Positions:

chrX-136209921-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4BS1_SupportingBS2

The NM_001159699.2(FHL1):c.787G>A(p.Asp263Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,208,369 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D263D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000015 ( 0 hom. 3 hem. )

Consequence

FHL1
NM_001159699.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.76

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001159699.2

BP4

Computational evidence support a benign effect (MetaRNN=0.30665517).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000998 (11/110218) while in subpopulation AMR AF= 0.00029 (3/10336). AF 95% confidence interval is 0.0000858. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159699.2 linkuse as main transcript	c.787G>A	p.Asp263Asn	missense_variant	6/6	ENST00000370683.6
FHL1	NM_001159702.3 linkuse as main transcript	c.939G>A	p.Thr313=	synonymous_variant	8/8	ENST00000394155.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000370683.6 linkuse as main transcript	c.787G>A	p.Asp263Asn	missense_variant	6/6	1	NM_001159699.2	P1	Q13642-5
FHL1	ENST00000394155.8 linkuse as main transcript	c.939G>A	p.Thr313=	synonymous_variant	8/8	5	NM_001159702.3		Q13642-2

Frequencies

GnomAD3 genomes

AF:

0.0000908

AC:

AN:

110168

Hom.:

Cov.:

AF XY:

0.0000308

AC XY:

AN XY:

32438

show subpopulations

Gnomad AFR

AF:

0.000198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000194

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.000679

GnomAD3 exomes

AF:

0.0000709

AC:

AN:

183475

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

67913

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1098151

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

363509

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.000256

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000998

AC:

AN:

110218

Hom.:

Cov.:

AF XY:

0.0000615

AC XY:

AN XY:

32498

show subpopulations

Gnomad4 AFR

AF:

0.000198

Gnomad4 AMR

AF:

0.000290

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000189

Gnomad4 OTH

AF:

0.000671

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Aug 11, 2021

- -

X-linked myopathy with postural muscle atrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 247 of the FHL1 protein (p.Asp247Asn). This variant is present in population databases (rs754308516, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. 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: 198467). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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

Eurofins Ntd Llc (ga)

Nov 26, 2014

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2023

The p.D247N variant (also known as c.739G>A), located in coding exon 5 of the FHL1 gene, results from a G to A substitution at nucleotide position 739. The aspartic acid at codon 247 is replaced by asparagine, an amino acid with highly similar properties. Based on data from gnomAD, the A allele has an overall frequency of 0.007% (14/204575) total alleles studied, with 3 hemizygote(s) observed. The highest observed frequency was 0.032% (9/28039) of Latino alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

.;.;.;.;.;.;.;.;T;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.80

.;.;.;.;.;T;T;T;D;.

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.31

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.14

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PROVEAN

Benign

0.25

.;N;.;N;N;N;N;N;N;.

REVEL

Uncertain

0.42

Sift

Benign

0.98

.;T;.;T;T;T;T;T;T;.

Sift4G

Benign

0.88

T;T;T;T;T;T;T;T;T;T

Vest4

0.29

MVP

0.98

ClinPred

0.078

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over