chr8-79765553-A-G

Position:

• chr8-79765553-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012258.4(HEY1):​c.550T>C​(p.Phe184Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HEY1 NM_012258.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEY1	NM_012258.4	c.550T>C	p.Phe184Leu	missense_variant	5/5	ENST00000354724.8	NP_036390.3
HEY1	NM_001040708.2	c.562T>C	p.Phe188Leu	missense_variant	5/5		NP_001035798.1
HEY1	NM_001282851.2	c.280T>C	p.Phe94Leu	missense_variant	2/2		NP_001269780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEY1	ENST00000354724.8	c.550T>C	p.Phe184Leu	missense_variant	5/5	1	NM_012258.4	ENSP00000346761.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2024

The c.550T>C (p.F184L) alteration is located in exon 5 (coding exon 5) of the HEY1 gene. This alteration results from a T to C substitution at nucleotide position 550, causing the phenylalanine (F) at amino acid position 184 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.;T;.
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	N;N;D;N
REVEL	Benign	0.18
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.0040	B;B;.;.
Vest4		0.41
MutPred		0.42		Gain of disorder (P = 0.0877);.;.;.;
MVP		0.37
MPC		0.60
ClinPred		0.91	D
GERP RS		5.7
Varity_R		0.34
gMVP		0.52

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-80677788;