NM_004821.3:c.531G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004821.3(HAND1):c.531G>C(p.Arg177Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0548 in 1,613,830 control chromosomes in the GnomAD database, including 2,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 214 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2539 hom. )

Consequence

HAND1
NM_004821.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.17

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: MODERATE Submitted by: ClinGen

HAND1 links:

ENSG00000306071 (HGNC:):

ENSG00000306071 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 5-154477478-C-G is Benign according to our data. Variant chr5-154477478-C-G is described in ClinVar as Benign. ClinVar VariationId is 413857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.17 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0586 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004821.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAND1	NM_004821.3	MANE Select	c.531G>C	p.Arg177Arg	synonymous	Exon 1 of 2	NP_004812.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAND1	ENST00000231121.3	TSL:1 MANE Select	c.531G>C	p.Arg177Arg	synonymous	Exon 1 of 2	ENSP00000231121.2
	ENSG00000306071	ENST00000815094.1		n.138C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0435

AC:

6622

AN:

152168

Hom.:

214

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0103

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.0499

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.0288

Gnomad FIN

AF:

0.0907

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0601

Gnomad OTH

AF:

0.0430

GnomAD2 exomes

AF:

0.0465

AC:

11617

AN:

249954

AF XY:

0.0471

show subpopulations

Gnomad AFR exome

AF:

0.00918

Gnomad AMR exome

AF:

0.0511

Gnomad ASJ exome

AF:

0.0198

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0831

Gnomad NFE exome

AF:

0.0574

Gnomad OTH exome

AF:

0.0466

GnomAD4 exome

AF:

0.0559

AC:

81742

AN:

1461544

Hom.:

2539

Cov.:

AF XY:

0.0554

AC XY:

40251

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.00807

AC:

270

AN:

33476

American (AMR)

AF:

0.0529

AC:

2366

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

580

AN:

26136

East Asian (EAS)

AF:

0.000479

AC:

AN:

39700

South Asian (SAS)

AF:

0.0331

AC:

2859

AN:

86254

European-Finnish (FIN)

AF:

0.0790

AC:

4217

AN:

53368

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0617

AC:

68593

AN:

1111736

Other (OTH)

AF:

0.0457

AC:

2760

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

4021

8043

12064

16086

20107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2540

5080

7620

10160

12700

<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:

0.0435

AC:

6620

AN:

152286

Hom.:

214

Cov.:

AF XY:

0.0446

AC XY:

3325

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0102

AC:

425

AN:

41572

American (AMR)

AF:

0.0500

AC:

765

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3472

East Asian (EAS)

AF:

0.00212

AC:

AN:

5178

South Asian (SAS)

AF:

0.0284

AC:

137

AN:

4818

European-Finnish (FIN)

AF:

0.0907

AC:

963

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0601

AC:

4089

AN:

68012

Other (OTH)

AF:

0.0426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

329

657

986

1314

1643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0513

Hom.:

Bravo

AF:

0.0386

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0517

EpiControl

AF:

0.0539

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

HAND1-related disorder

Benign:1

Jul 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

not specified

Benign:1

Oct 09, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypoplastic left heart syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

1.2

Mutation Taster

=85/15

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over