rs201302313

Variant summary

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

The NM_004821.3(HAND1):c.247G>T(p.Gly83Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,607,860 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts 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. G83R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 5 hom. )

Consequence

HAND1
NM_004821.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.311

Variant links:

Genes affected

HAND1 (HGNC:4807): (heart and neural crest derivatives expressed 1) The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins, which are asymmetrically expressed in the developing ventricular chambers and play an essential role in cardiac morphogenesis. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries, implicating them as mediators of congenital heart disease. In addition, it has been suggested that this transcription factor may be required for early trophoblast differentiation. [provided by RefSeq, Jul 2008]

HAND1 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=0.011764228).

BP6

Variant 5-154477762-C-A is Benign according to our data. Variant chr5-154477762-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 252637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-154477762-C-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 258 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAND1	NM_004821.3 linkuse as main transcript	c.247G>T	p.Gly83Trp	missense_variant	1/2	ENST00000231121.3
HAND1	XM_005268531.2 linkuse as main transcript	c.247G>T	p.Gly83Trp	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAND1	ENST00000231121.3 linkuse as main transcript	c.247G>T	p.Gly83Trp	missense_variant	1/2	1	NM_004821.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00170

AC:

258

AN:

151574

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00439

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00280

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00145

AC:

337

AN:

232082

Hom.:

AF XY:

0.00152

AC XY:

194

AN XY:

127364

show subpopulations

Gnomad AFR exome

AF:

0.000283

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000309

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000298

Gnomad FIN exome

AF:

0.00463

Gnomad NFE exome

AF:

0.00220

Gnomad OTH exome

AF:

0.00157

GnomAD4 exome

AF:

0.00171

AC:

2489

AN:

1456170

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

1231

AN XY:

724504

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.000422

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00455

Gnomad4 NFE exome

AF:

0.00194

Gnomad4 OTH exome

AF:

0.00115

GnomAD4 genome

AF:

0.00170

AC:

258

AN:

151690

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

123

AN XY:

74136

show subpopulations

Gnomad4 AFR

AF:

0.000218

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00439

Gnomad4 NFE

AF:

0.00280

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00220

Hom.:

Bravo

AF:

0.000975

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00146

AC:

176

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 10, 2015

- -

HAND1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypoplastic left heart syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Benign

0.17

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.012

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

0.90

MutationTaster

Benign

0.96

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.91

Vest4

0.26

MVP

0.95

MPC

1.5

ClinPred

0.042

GERP RS

5.0

Varity_R

0.47

gMVP

0.53

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