rs1553974835

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-173529091-C-A
• chr4-173529091-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_021973.3(HAND2):​c.199G>T​(p.Glu67*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HAND2 NM_021973.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.81

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-173529091-C-A is Pathogenic according to our data. Variant chr4-173529091-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 545687.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-173529091-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAND2	NM_021973.3	c.199G>T	p.Glu67*	stop_gained	Exon 1 of 2	ENST00000359562.4	NP_068808.1
HAND2-AS1	NR_136197.1	n.240+252C>A		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAND2	ENST00000359562.4	c.199G>T	p.Glu67*	stop_gained	Exon 1 of 2	1	NM_021973.3	ENSP00000352565.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1359164 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 672130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1A Pathogenic:1

May 29, 2018

Cardiovascular Research Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control;in vitro

The p.Glu67* variant in HAND2 was identified in 1 Chinese family with autosomal dominant dilated cardiomyopathy, segregated with the disease with complete penetrance, and was absent from the 300 healthy controls. Additionally, in vitro functional studies indicated that the p.Glu67* variant disrupted normal transcriptional function. In summary, the p.Glu67* variant meets our criteria to be classified as pathogenic (www.partners.org/personalizedmedicine/lmm) based upon segregation studies, absence from controls, and functional evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.67
GERP RS		3.9

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: rs1553974835; hg19: chr4-174450242;