rs753971979

Variant names:

• chr1-39626914-C-A
• rs753971979
• NM_014571.4:c.580G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-39626914-C-A
• chr1-39626914-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014571.4(HEYL):​c.580G>T​(p.Ala194Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. A194D) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: HEYL NM_014571.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.133
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.076456666).

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.580G>T	p.Ala194Ser	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.580G>T	p.Ala194Ser	missense	Exon 5 of 5	ENSP00000361943.3	Q9NQ87
	HEYL	ENST00000851853.1		c.610G>T	p.Ala204Ser	missense	Exon 5 of 5	ENSP00000521912.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151998 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151998 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74248

African (AFR) AF: 0.00 AC: 0 AN: 41374

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.5
DANN	Benign	0.65
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.13
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.036
Sift	Benign	0.10	T
Sift4G	Benign	0.62	T
Polyphen		0.049	B
Vest4		0.046
MutPred		0.39		Gain of disorder (P = 0.0291)
MVP		0.58
MPC		0.19
ClinPred		0.34	T
GERP RS		1.7
Varity_R		0.027
gMVP		0.24
Mutation Taster		=99/1	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: rs753971979; hg19: chr1-40092586;