4-173527393-G-C

Position:

• chr4-173527393-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000359562.4(HAND2):​c.556-18C>G variant causes a intron change. The variant allele was found at a frequency of 0.0124 in 1,563,460 control chromosomes in the GnomAD database, including 182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (11 hom., cov: 32)
  • Exomes 𝑓: 0.013 (171 hom.)
• Consequence: HAND2 ENST00000359562.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.00

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 4-173527393-G-C is Benign according to our data. Variant chr4-173527393-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1331143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1318 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAND2	NM_021973.3	c.556-18C>G		intron_variant		ENST00000359562.4	NP_068808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAND2	ENST00000359562.4	c.556-18C>G		intron_variant		1	NM_021973.3	ENSP00000352565	P1
HAND2-AS1	ENST00000512099.5	n.124G>C		non_coding_transcript_exon_variant	1/4	2
HAND2	ENST00000503024.1	c.179-18C>G		intron_variant, NMD_transcript_variant		3		ENSP00000427084

Frequencies

GnomAD3 genomes AF: 0.00866 AC: 1318 AN: 152158 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00857 AC: 2132 AN: 248852 Hom.: 11 AF XY: 0.00858 AC XY: 1156 AN XY: 134736

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0139

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0128 AC: 18098 AN: 1411184 Hom.: 171 Cov.: 24 AF XY: 0.0124 AC XY: 8743 AN XY: 705064

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.00419

Gnomad4 ASJ exome AF: 0.00651

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000493

Gnomad4 FIN exome AF: 0.0169

Gnomad4 NFE exome AF: 0.0150

Gnomad4 OTH exome AF: 0.0119

GnomAD4 genome AF: 0.00866 AC: 1318 AN: 152276 Hom.: 11 Cov.: 32 AF XY: 0.00806 AC XY: 600 AN XY: 74466

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0109

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.0112 Hom.: 2

Bravo AF: 0.00783

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs115738185; hg19: chr4-174448544;