4-173528900-G-T

Variant names:

• chr4-173528900-G-T
• rs483353128
• NM_021973.3:c.390C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP5 BP4 BP7

The NM_021973.3(HAND2):​c.390C>A​(p.Pro130Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HAND2 NM_021973.3 synonymous
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.599
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-173528900-G-T is Pathogenic according to our data. Variant chr4-173528900-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 139597.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51). . Strength limited to SUPPORTING due to the PP5.
• BP7: Synonymous conserved (PhyloP=0.599 with no splicing effect.

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.390C>A	p.Pro130Pro	synonymous	Exon 1 of 2	NP_068808.1	P61296-1
	HAND2-AS1	NR_136197.1		n.240+61G>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.390C>A	p.Pro130Pro	synonymous	Exon 1 of 2	ENSP00000352565.4	P61296-1
	HAND2	ENST00000503024.1	TSL:3	n.12C>A		non_coding_transcript_exon	Exon 1 of 4	ENSP00000427084.1	H0YAH1
	HAND2	ENST00000505300.1	TSL:5	n.552C>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		0.60

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: rs483353128; hg19: chr4-174450051;