chr5-154477752-T-G

Variant names:

• chr5-154477752-T-G
• rs1177737621
• NM_004821.3:c.257A>C

Variant summary

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

The NM_004821.3(HAND1):​c.257A>C​(p.Glu86Ala) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E86V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HAND1 NM_004821.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.546
• Publications: 0 publications found

Genes affected

HAND1 (HGNC:4807): (heart and neural crest derivatives expressed 1) 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, it has been suggested that this transcription factor may be required for early trophoblast differentiation. [provided by RefSeq, Jul 2008]

HAND1 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ENSG00000306071 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30077973).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAND1	NM_004821.3	c.257A>C	p.Glu86Ala	missense_variant	Exon 1 of 2	ENST00000231121.3	NP_004812.1
HAND1	XM_005268531.2	c.257A>C	p.Glu86Ala	missense_variant	Exon 1 of 2		XP_005268588.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAND1	ENST00000231121.3	c.257A>C	p.Glu86Ala	missense_variant	Exon 1 of 2	1	NM_004821.3	ENSP00000231121.2
ENSG00000306071	ENST00000815094.1	n.233+179T>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.079
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.0	L
PhyloP100		0.55
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.87	N
REVEL	Uncertain	0.38
Sift	Benign	0.25	T
Sift4G	Benign	0.75	T
Polyphen		0.46	P
Vest4		0.21
MutPred		0.26		Gain of MoRF binding (P = 0.0388);
MVP		0.94
MPC		0.62
ClinPred		0.39	T
GERP RS		5.0
PromoterAI		0.077	Neutral
Varity_R		0.30
gMVP		0.56
Mutation Taster		=59/41	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: rs1177737621; hg19: chr5-153857312;