X-136209951-G-C

Position:

chrX-136209951-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001159699.2(FHL1):c.817G>C(p.Val273Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 1,208,774 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/14 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: 𝑓 0.000045 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000035 ( 0 hom. 14 hem. )

Consequence

FHL1
NM_001159699.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.21

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:

FHL1 (HGNC:):

FHL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16958019).

BP6

Variant X-136209951-G-C is Benign according to our data. Variant chrX-136209951-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 838540.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chrX-136209951-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000452 (5/110563) while in subpopulation NFE AF= 0.0000945 (5/52906). AF 95% confidence interval is 0.0000371. There are 0 homozygotes in gnomad4. There are 0 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHL1	NM_001159699.2 linkuse as main transcript	c.817G>C	p.Val273Leu	missense_variant	6/6	ENST00000370683.6	NP_001153171.1	Q13642-5
FHL1	NM_001159702.3 linkuse as main transcript	c.969G>C	p.Pro323Pro	synonymous_variant	8/8	ENST00000394155.8	NP_001153174.1	Q13642-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000370683.6 linkuse as main transcript	c.817G>C	p.Val273Leu	missense_variant	6/6	1	NM_001159699.2	ENSP00000359717.1		Q13642-5
FHL1	ENST00000394155.8 linkuse as main transcript	c.969G>C	p.Pro323Pro	synonymous_variant	8/8	5	NM_001159702.3	ENSP00000377710.2		Q13642-2

Frequencies

GnomAD3 genomes

AF:

0.0000452

AC:

AN:

110563

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32807

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000945

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000436

AC:

AN:

183526

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

67954

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000109

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:

0.0000366

Gnomad OTH exome

AF:

0.000441

GnomAD4 exome

AF:

0.0000346

AC:

AN:

1098211

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

363565

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

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:

0.0000392

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000452

AC:

AN:

110563

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32807

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000945

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

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

Jan 15, 2024

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 257 of the FHL1 protein (p.Val257Leu). This variant is present in population databases (rs190006104, gnomAD 0.01%). 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: 838540). 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 leucine 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2023

The p.V257L variant (also known as c.769G>C), located in coding exon 5 of the FHL1 gene, results from a G to C substitution at nucleotide position 769. The valine at codon 257 is replaced by leucine, an amino acid with highly similar properties. Based on data from gnomAD, the C allele has an overall frequency of <0.01% (8/183526) total alleles studied, with 4 hemizygote(s) observed. The highest observed frequency was 0.01% (3/27431) of Latino alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.0035

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.20

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

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.86

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

M_CAP

Benign

0.014

MetaRNN

Benign

0.14

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

MetaSVM

Benign

-0.83

PROVEAN

Benign

-0.85

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

REVEL

Uncertain

0.34

Sift

Benign

0.88

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

Sift4G

Benign

0.67

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

Vest4

0.16

MutPred

0.38

.;.;.;.;.;.;Loss of catalytic residue at V286 (P = 0.0428);.;.;.;

MVP

0.84

ClinPred

0.018

GERP RS

-0.74

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

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