4-173528787-T-C

Variant names:

• chr4-173528787-T-C
• rs1731591019
• NM_021973.3:c.503A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021973.3(HAND2):​c.503A>G​(p.Lys168Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: HAND2 NM_021973.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

Genes affected

HAND2 (HGNC:4808): (heart and neural crest derivatives expressed 2) 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, this transcription factor plays an important role in limb and branchial arch development. [provided by RefSeq, Jul 2008]

HAND2-AS1 (HGNC:48872): (HAND2 antisense RNA 1) Predicted to be involved in positive regulation of gene expression. Predicted to act upstream of or within with a positive effect on cardiac right ventricle morphogenesis. Predicted to act upstream of or within transcription elongation from RNA polymerase II promoter. Predicted to be located in chromatin; cytoplasm; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21226013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAND2	NM_021973.3	c.503A>G	p.Lys168Arg	missense_variant	Exon 1 of 2	ENST00000359562.4	NP_068808.1
HAND2-AS1	NR_136197.1	n.188T>C		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAND2	ENST00000359562.4	c.503A>G	p.Lys168Arg	missense_variant	Exon 1 of 2	1	NM_021973.3	ENSP00000352565.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with HAND2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 168 of the HAND2 protein (p.Lys168Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.68	N;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.96	N;.
REVEL	Uncertain	0.53
Sift	Benign	0.40	T;.
Sift4G	Benign	0.80	T;T
Polyphen		0.063	B;.
Vest4		0.36
MutPred		0.33		Loss of ubiquitination at K168 (P = 0.0059);.;
MVP		0.94
MPC		0.80
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.30
gMVP		0.57

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

Other links and lift over

dbSNP: rs1731591019; hg19: chr4-174449938;