rs764180477

Variant names:

• chr1-39626841-C-G
• rs764180477
• NM_014571.4:c.653G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-39626841-C-G
• chr1-39626841-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014571.4(HEYL):​c.653G>C​(p.Arg218Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,650 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R218G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: HEYL NM_014571.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• Publications: 0 publications found

Genes affected

HEYL (HGNC:4882): (hes related family bHLH transcription factor with YRPW motif like) This gene encodes a member of the hairy and enhancer of split-related (HESR) family of basic helix-loop-helix (bHLH)-type transcription factors. The sequence of the encoded protein contains a conserved bHLH and orange domain, but its YRPW motif has diverged from other HESR family members. It is thought to be an effector of Notch signaling and a regulator of cell fate decisions. Alternatively spliced transcript variants have been found, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014571.4. 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
	HEYL	NM_014571.4	MANE Select	c.653G>C	p.Arg218Pro	missense	Exon 5 of 5	NP_055386.2	Q9NQ87

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEYL	ENST00000372852.4	TSL:1 MANE Select	c.653G>C	p.Arg218Pro	missense	Exon 5 of 5	ENSP00000361943.3	Q9NQ87
	HEYL	ENST00000851853.1		c.683G>C	p.Arg228Pro	missense	Exon 5 of 5	ENSP00000521912.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424650 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 704910

African (AFR) AF: 0.00 AC: 0 AN: 32838

American (AMR) AF: 0.00 AC: 0 AN: 37788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25250

East Asian (EAS) AF: 0.00 AC: 0 AN: 38020

South Asian (SAS) AF: 0.00 AC: 0 AN: 81644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1092956

Other (OTH) AF: 0.00 AC: 0 AN: 59160

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.50
MutPred		0.30		Gain of glycosylation at R218 (P = 0.022)
MVP		0.80
MPC		0.80
ClinPred		0.89	D
GERP RS		5.0
Varity_R		0.31
gMVP		0.77
Mutation Taster		=82/18	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: rs764180477; hg19: chr1-40092513;