Variant rs1343871742 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001159702.3(FHL1):c.175C>A(p.Arg59Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 111,866 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Consequence

FHL1
NM_001159702.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHL1	NM_001159702.3 linkuse as main transcript	c.175C>A	p.Arg59Ser	missense_variant	4/8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2 linkuse as main transcript	c.223C>A	p.Arg75Ser	missense_variant	3/6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8 linkuse as main transcript	c.175C>A	p.Arg59Ser	missense_variant	4/8	5	NM_001159702.3	ENSP00000377710		Q13642-2
FHL1	ENST00000370683.6 linkuse as main transcript	c.223C>A	p.Arg75Ser	missense_variant	3/6	1	NM_001159699.2	ENSP00000359717	P1	Q13642-5

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111866

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34048

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:

0.000285

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111866

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34048

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000285

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2024

The p.R59S variant (also known as c.175C>A), located in coding exon 2 of the FHL1 gene, results from a C to A substitution at nucleotide position 175. The arginine at codon 59 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on data from gnomAD, the A allele has an overall frequency of <0.01% (1/21673) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.10% (1/975) of East Asian alleles. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

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

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.91

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;D;D

MetaSVM

Uncertain

0.57

MutationAssessor

Uncertain

2.3

M;M;M;.;M;.;.;.;.;M;.;.;M;.;.;M;M;.;.;.;M;.;.;.;.;.;M

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.0

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

REVEL

Pathogenic

0.90

Sift

Uncertain

0.014

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

Sift4G

Uncertain

0.0080

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

Polyphen

0.99

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

Vest4

0.85

MutPred

0.72

Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);.;.;.;Loss of MoRF binding (P = 0.0572);Loss of MoRF binding (P = 0.0572);

MVP

1.0

MPC

1.4

ClinPred

0.85

GERP RS

5.1

Varity_R

0.87

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

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