rs190006104

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1BP4_ModerateBS1_SupportingBS2

The NM_001159699.2(FHL1):c.817G>A(p.Val273Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,208,828 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V273L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000031 ( 0 hom. 10 hem. )

Consequence

FHL1
NM_001159699.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.21

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

X-linked myopathy with postural muscle atrophy
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
myopathy, reducing body, X-linked, early-onset, severe
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
reducing body myopathy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked Emery-Dreifuss muscular dystrophy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked scapuloperoneal muscular dystrophy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

FHL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 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, 17 uncertain in NM_001159699.2

BP4

Computational evidence support a benign effect (MetaRNN=0.15596738).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000031 (34/1098211) while in subpopulation NFE AF = 0.000038 (32/842100). AF 95% confidence interval is 0.0000275. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159699.2 link	c.817G>A	p.Val273Met	missense_variant	Exon 6 of 6	ENST00000370683.6	NP_001153171.1	Q13642-5
FHL1	NM_001159702.3 link	c.969G>A	p.Pro323Pro	synonymous_variant	Exon 8 of 8	ENST00000394155.8	NP_001153174.1	Q13642-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000370683.6 link	c.817G>A	p.Val273Met	missense_variant	Exon 6 of 6	1	NM_001159699.2	ENSP00000359717.1		Q13642-5
FHL1	ENST00000394155.8 link	c.969G>A	p.Pro323Pro	synonymous_variant	Exon 8 of 8	5	NM_001159702.3	ENSP00000377710.2		Q13642-2

Frequencies

GnomAD3 genomes

AF:

0.0000181

AC:

AN:

110563

Hom.:

Cov.:

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:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000163

AC:

AN:

183526

AF XY:

0.0000147

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000310

AC:

AN:

1098211

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

363565

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.0000284

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000380

AC:

AN:

842100

Other (OTH)

AF:

0.0000217

AC:

AN:

46094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000181

AC:

AN:

110617

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32871

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30380

American (AMR)

AF:

0.00

AC:

AN:

10399

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2630

East Asian (EAS)

AF:

0.00

AC:

AN:

3530

South Asian (SAS)

AF:

0.00

AC:

AN:

2573

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

52899

Other (OTH)

AF:

0.00

AC:

AN:

1505

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked myopathy with postural muscle atrophy

Uncertain:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 257 of the FHL1 protein (p.Val257Met). This variant is present in population databases (rs190006104, gnomAD 0.006%). 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: 569001). 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 tolerated. 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. -

FHL1-related disorder

Uncertain:1

May 17, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The FHL1 c.817G>A variant is predicted to result in the amino acid substitution p.Val273Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0053% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Mar 30, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.769G>A (p.V257M) alteration is located in exon 7 (coding exon 5) of the FHL1 gene. This alteration results from a G to A substitution at nucleotide position 769, causing the valine (V) at amino acid position 257 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

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

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.87

.;.;.;.;.;D;D;D;D;.

M_CAP

Benign

0.038

MetaRNN

Benign

0.13

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

MetaSVM

Benign

-0.54

PhyloP100

1.2

PROVEAN

Benign

-1.1

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

REVEL

Benign

0.27

Sift

Benign

0.042

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

Sift4G

Uncertain

0.056

T;T;T;T;T;T;T;T;D;T

Vest4

0.20

MVP

0.87

ClinPred

0.069

GERP RS

-0.74

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over