8-79766192-T-A

Variant names:

• chr8-79766192-T-A
• rs2440624
• NM_012258.4:c.332-421A>T

Variant summary

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

The NM_012258.4(HEY1):​c.332-421A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,378,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: HEY1 NM_012258.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.231
• Publications: 0 publications found

Genes affected

HEY1 (HGNC:4880): (hes related family bHLH transcription factor with YRPW motif 1) This gene encodes a nuclear protein belonging to the hairy and enhancer of split-related (HESR) family of basic helix-loop-helix (bHLH)-type transcriptional repressors. Expression of this gene is induced by the Notch and c-Jun signal transduction pathways. Two similar and redundant genes in mouse are required for embryonic cardiovascular development, and are also implicated in neurogenesis and somitogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

LINC01607 (HGNC:51660): (long intergenic non-protein coding RNA 1607)

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 (BayesDel_noAF=-0.16).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012258.4. 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
	HEY1	NM_012258.4	MANE Select	c.332-421A>T		intron	N/A	NP_036390.3
	HEY1	NM_001040708.2		c.344-421A>T		intron	N/A	NP_001035798.1	Q9Y5J3-2
	HEY1	NM_001282851.2		c.61+11A>T		intron	N/A	NP_001269780.1	B4DEI9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEY1	ENST00000354724.8	TSL:1 MANE Select	c.332-421A>T		intron	N/A	ENSP00000346761.3	Q9Y5J3-1
	HEY1	ENST00000337919.9	TSL:1	c.344-421A>T		intron	N/A	ENSP00000338272.5	Q9Y5J3-2
	HEY1	ENST00000435063.4	TSL:1	n.142+175A>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1378456 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 680138

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31346

American (AMR) AF: 0.00 AC: 0 AN: 34978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25020

East Asian (EAS) AF: 0.00 AC: 0 AN: 35704

South Asian (SAS) AF: 0.00 AC: 0 AN: 78096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076462

Other (OTH) AF: 0.00 AC: 0 AN: 57732

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.16
CADD	Benign	16
DANN	Benign	0.80
PhyloP100		0.23
PromoterAI		-0.0094	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2440624; hg19: chr8-80678427;