rs139625615

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001159702.3(FHL1):c.205G>A(p.Ala69Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000892 in 1,210,180 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/20 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. A69G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000094 ( 0 hom. 29 hem. )

Consequence

FHL1
NM_001159702.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.213

Publications

2 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06107995).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000446 (5/112087) while in subpopulation EAS AF = 0.00143 (5/3499). AF 95% confidence interval is 0.000562. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 24. 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 29 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3 link	c.205G>A	p.Ala69Thr	missense_variant	Exon 4 of 8	ENST00000394155.8	NP_001153174.1	Q13642-2
FHL1	NM_001159699.2 link	c.253G>A	p.Ala85Thr	missense_variant	Exon 3 of 6	ENST00000370683.6	NP_001153171.1	Q13642-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8 link	c.205G>A	p.Ala69Thr	missense_variant	Exon 4 of 8	5	NM_001159702.3	ENSP00000377710.2		Q13642-2
FHL1	ENST00000370683.6 link	c.253G>A	p.Ala85Thr	missense_variant	Exon 3 of 6	1	NM_001159699.2	ENSP00000359717.1		Q13642-5

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112033

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:

0.00142

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000546

AC:

AN:

183118

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000938

AC:

103

AN:

1098093

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

363487

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00331

AC:

100

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54139

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40511

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4060

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842108

Other (OTH)

AF:

0.0000651

AC:

AN:

46088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000446

AC:

AN:

112087

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34283

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30856

American (AMR)

AF:

0.00

AC:

AN:

10681

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00143

AC:

AN:

3499

South Asian (SAS)

AF:

0.00

AC:

AN:

2636

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53182

Other (OTH)

AF:

0.00

AC:

AN:

1532

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.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked myopathy with postural muscle atrophy

Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 69 of the FHL1 protein (p.Ala69Thr). This variant is not present in population databases (gnomAD no frequency). 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: 537354). 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. -

not provided

Uncertain:1

Jun 06, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Apr 11, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A69T variant (also known as c.205G>A), located in coding exon 2 of the FHL1 gene, results from a G to A substitution at nucleotide position 205. The alanine at codon 69 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated 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

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Benign

9.6

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.28

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

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.89

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

M_CAP

Benign

0.061

MetaRNN

Benign

0.061

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

-0.33

MutationAssessor

Benign

1.4

L;L;L;.;L;.;.;.;.;L;.;.;L;.;L;L;.;.;.;L;.;.;.;.;.;L

PhyloP100

0.21

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.34

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

REVEL

Benign

0.25

Sift

Benign

0.27

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

Sift4G

Benign

1.0

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

0.11, 0.014

.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;B;.;.;.;B;.;.

Vest4

0.25

MVP

0.82

MPC

0.48

ClinPred

0.15

GERP RS

1.7

Varity_R

0.065

Mutation Taster

=45/55

disease causing

(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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rs139625615

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