1-39626913-G-T

Variant names:

• chr1-39626913-G-T
• rs1208116260
• NM_014571.4:c.581C>A

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.581C>A​(p.Ala194Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A194T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HEYL NM_014571.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.71
• 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=0.25322956).

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.581C>A	p.Ala194Asp	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.581C>A	p.Ala194Asp	missense	Exon 5 of 5	ENSP00000361943.3	Q9NQ87
	HEYL	ENST00000851853.1		c.611C>A	p.Ala204Asp	missense	Exon 5 of 5	ENSP00000521912.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.43	T
Polyphen		0.090	B
Vest4		0.22
MutPred		0.40		Gain of solvent accessibility (P = 0.194)
MVP		0.75
MPC		0.36
ClinPred		0.42	T
GERP RS		5.0
Varity_R		0.28
gMVP		0.42
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1208116260; hg19: chr1-40092585;