4-173529091-C-T

Variant names:

• chr4-173529091-C-T
• rs1553974835
• NM_021973.3:c.199G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021973.3(HAND2):​c.199G>A​(p.Glu67Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000736 in 1,359,164 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: HAND2 NM_021973.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.81
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021973.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAND2	NM_021973.3	MANE Select	c.199G>A	p.Glu67Lys	missense	Exon 1 of 2	NP_068808.1	P61296-1
	HAND2-AS1	NR_136197.1		n.240+252C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAND2	ENST00000359562.4	TSL:1 MANE Select	c.199G>A	p.Glu67Lys	missense	Exon 1 of 2	ENSP00000352565.4	P61296-1
	HAND2	ENST00000505300.1	TSL:5	n.361G>A		non_coding_transcript_exon	Exon 3 of 3
	HAND2-AS1	ENST00000512099.5	TSL:2	n.1232+590C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.36e-7 AC: 1 AN: 1359164 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 672130

African (AFR) AF: 0.00 AC: 0 AN: 27336

American (AMR) AF: 0.00 AC: 0 AN: 25236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19868

East Asian (EAS) AF: 0.00 AC: 0 AN: 36426

South Asian (SAS) AF: 0.00 AC: 0 AN: 68842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3946

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1073688

Other (OTH) AF: 0.00 AC: 0 AN: 55574

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.083
Eigen_PC	Benign	0.0085
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.59
Sift	Benign	0.28	T
Sift4G	Benign	0.23	T
Polyphen		0.45	B
Vest4		0.33
MutPred		0.31		Gain of ubiquitination at E67 (P = 0.0082)
MVP		0.92
MPC		1.1
ClinPred		0.87	D
GERP RS		3.9
Varity_R		0.43
gMVP		0.71
Mutation Taster		=73/27	polymorphism

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: rs1553974835; hg19: chr4-174450242;