NM_004821.3:c.468T>G

Variant names:

• chr5-154477541-A-C
• rs34402828
• NM_004821.3:c.468T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004821.3(HAND1):​c.468T>G​(p.Ser156Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 1,614,134 control chromosomes in the GnomAD database, including 2,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S156S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.045 (180 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2596 hom.)
• Consequence: HAND1 NM_004821.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0570
• Publications: 7 publications found

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

ENSG00000306071 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 5-154477541-A-C is Benign according to our data. Variant chr5-154477541-A-C is described in ClinVar as Benign. ClinVar VariationId is 413856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.057 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0642 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.468T>G	p.Ser156Ser	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.468T>G	p.Ser156Ser	synonymous	Exon 1 of 2	ENSP00000231121.2
	ENSG00000306071	ENST00000815094.1		n.201A>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6829 AN: 152160 Hom.: 181 Cov.: 33

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.0733

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0658

Gnomad OTH AF: 0.0507

GnomAD2 exomes AF: 0.0466 AC: 11721 AN: 251346 AF XY: 0.0473

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.0411

Gnomad ASJ exome AF: 0.0837

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0493

Gnomad NFE exome AF: 0.0638

Gnomad OTH exome AF: 0.0612

GnomAD4 exome AF: 0.0562 AC: 82192 AN: 1461856 Hom.: 2596 Cov.: 34 AF XY: 0.0555 AC XY: 40372 AN XY: 727236

African (AFR) AF: 0.00911 AC: 305 AN: 33480

American (AMR) AF: 0.0431 AC: 1928 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0784 AC: 2049 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0184 AC: 1585 AN: 86258

European-Finnish (FIN) AF: 0.0481 AC: 2567 AN: 53418

Middle Eastern (MID) AF: 0.0498 AC: 287 AN: 5768

European-Non Finnish (NFE) AF: 0.0631 AC: 70156 AN: 1111976

Other (OTH) AF: 0.0548 AC: 3309 AN: 60396

GnomAD4 genome AF: 0.0448 AC: 6827 AN: 152278 Hom.: 180 Cov.: 33 AF XY: 0.0437 AC XY: 3251 AN XY: 74468

African (AFR) AF: 0.0114 AC: 475 AN: 41572

American (AMR) AF: 0.0522 AC: 799 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0733 AC: 254 AN: 3466

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5172

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4820

European-Finnish (FIN) AF: 0.0512 AC: 543 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0658 AC: 4473 AN: 68018

Other (OTH) AF: 0.0501 AC: 106 AN: 2114

Alfa AF: 0.0528 Hom.: 278

Bravo AF: 0.0431

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0704

EpiControl AF: 0.0734

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypoplastic left heart syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.2
DANN	Benign	0.65
PhyloP100		0.057
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34402828; hg19: chr5-153857101;