chr8-79766258-AGGCATGT-A

Variant names:

• chr8-79766258-AGGCATGT-A
• rs142613628
• NM_012258.4:c.331+386_331+392delACATGCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001282851.2(HEY1):​c.-2_5delACATGCC​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,530,764 control chromosomes in the GnomAD database, including 11,511 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1270 hom., cov: 31)
  • Exomes 𝑓: 0.11 (10241 hom.)
• Consequence: HEY1 NM_001282851.2 frameshift, start_lost
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.792

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]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 8-79766258-AGGCATGT-A is Benign according to our data. Variant chr8-79766258-AGGCATGT-A is described in ClinVar as [Benign]. Clinvar id is 1232147.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEY1	NM_012258.4	c.331+386_331+392delACATGCC		intron_variant	Intron 4 of 4	ENST00000354724.8	NP_036390.3
HEY1	NM_001282851.2	c.-2_5delACATGCC	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 2		NP_001269780.1
HEY1	NM_001282851.2	c.-2_5delACATGCC		5_prime_UTR_variant	Exon 1 of 2		NP_001269780.1
HEY1	NM_001040708.2	c.343+386_343+392delACATGCC		intron_variant	Intron 4 of 4		NP_001035798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEY1	ENST00000354724.8	c.331+386_331+392delACATGCC		intron_variant	Intron 4 of 4	1	NM_012258.4	ENSP00000346761.3

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18786 AN: 152010 Hom.: 1274 Cov.: 31

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0901

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.0733 AC: 8601 AN: 117348 AF XY: 0.0841

Gnomad AFR exome AF: 0.0507

Gnomad AMR exome AF: 0.0334

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.000481

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.0608

Gnomad OTH exome AF: 0.0774

GnomAD4 exome AF: 0.113 AC: 155102 AN: 1378634 Hom.: 10241 AF XY: 0.117 AC XY: 79646 AN XY: 680170

Gnomad4 AFR exome AF: 0.152 AC: 4775 AN: 31376

Gnomad4 AMR exome AF: 0.0671 AC: 2374 AN: 35356

Gnomad4 ASJ exome AF: 0.204 AC: 5096 AN: 25026

Gnomad4 EAS exome AF: 0.000840 AC: 30 AN: 35730

Gnomad4 SAS exome AF: 0.242 AC: 18919 AN: 78238

Gnomad4 FIN exome AF: 0.124 AC: 4128 AN: 33412

Gnomad4 NFE exome AF: 0.104 AC: 111703 AN: 1076084

Gnomad4 Remaining exome AF: 0.125 AC: 7201 AN: 57732

GnomAD4 genome AF: 0.123 AC: 18784 AN: 152130 Hom.: 1270 Cov.: 31 AF XY: 0.126 AC XY: 9375 AN XY: 74386

Gnomad4 AFR AF: 0.155 AC: 0.154847 AN: 0.154847

Gnomad4 AMR AF: 0.0898 AC: 0.0898039 AN: 0.0898039

Gnomad4 ASJ AF: 0.197 AC: 0.197346 AN: 0.197346

Gnomad4 EAS AF: 0.00193 AC: 0.00192604 AN: 0.00192604

Gnomad4 SAS AF: 0.244 AC: 0.244065 AN: 0.244065

Gnomad4 FIN AF: 0.138 AC: 0.137557 AN: 0.137557

Gnomad4 NFE AF: 0.107 AC: 0.106935 AN: 0.106935

Gnomad4 OTH AF: 0.127 AC: 0.127488 AN: 0.127488

Alfa AF: 0.122 Hom.: 235

Bravo AF: 0.116

Asia WGS AF: 0.113 AC: 394 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

HEY1-related disorder Benign:1

Feb 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=190/10	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142613628; hg19: chr8-80678493; COSMIC: COSV61233341; COSMIC: COSV61233341;