rs74575749

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001318895.3(FHL2):c.109G>T(p.Ala37Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000333 in 1,614,160 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A37T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

FHL2
NM_001318895.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.55

Variant links:

Genes affected

FHL2 (HGNC:3703): (four and a half LIM domains 2) 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. This protein is thought to have a role in the assembly of extracellular membranes. Also, this gene is down-regulated during transformation of normal myoblasts to rhabdomyosarcoma cells and the encoded protein may function as a link between presenilin-2 and an intracellular signaling pathway. Multiple alternatively spliced variants encoding different isoforms have been identified. [provided by RefSeq, Jan 2016]

FHL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008567363).

BP6

Variant 2-105386408-C-A is Benign according to our data. Variant chr2-105386408-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 178038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-105386408-C-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 275 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL2	NM_001318895.3 linkuse as main transcript	c.109G>T	p.Ala37Ser	missense_variant	3/7	ENST00000530340.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL2	ENST00000530340.6 linkuse as main transcript	c.109G>T	p.Ala37Ser	missense_variant	3/7	1	NM_001318895.3	P1	Q14192-1

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

275

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00622

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

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:

0.0000735

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000469

AC:

118

AN:

251348

Hom.:

AF XY:

0.000427

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.000405

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000180

AC:

263

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

105

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00600

Gnomad4 AMR exome

AF:

0.000447

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:

0.0000171

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.00181

AC:

275

AN:

152320

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

141

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00621

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000271

Hom.:

Bravo

AF:

0.00190

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000585

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 19, 2012

Ala37Ser in exon 2 of FHL2: This variant is not expected to have clinical signif icance because it has been identified in 0.7% (26/3738) of African American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS; dbSNP rs74575749). Ala37Ser in exon 2 of FHL2 (rs74575 749; allele frequency = 0.7%, 26/3738) ** -

Primary dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

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

Eigen

Benign

-0.038

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

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

M_CAP

Benign

0.016

MetaRNN

Benign

0.0086

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

MetaSVM

Benign

-0.37

MutationAssessor

Benign

0.80

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

MutationTaster

Benign

0.99

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

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.5

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

REVEL

Uncertain

0.37

Sift

Benign

0.41

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

Sift4G

Benign

0.34

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

Polyphen

0.0040

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

Vest4

0.14

MVP

0.98

MPC

0.21

ClinPred

0.011

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

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