rs986079419

Variant names:

• chr1-999127-C-A
• rs986079419
• NM_021170.4:c.598G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-999127-C-A
• chr1-999127-C-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_021170.4(HES4):​c.598G>T​(p.Ala200Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000563 in 1,065,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A200P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: HES4 NM_021170.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.75
• Publications: 0 publications found

Genes affected

HES4 (HGNC:24149): (hes family bHLH transcription factor 4) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in anterior/posterior pattern specification and regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053687662).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021170.4. 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
	HES4	NM_021170.4	MANE Select	c.598G>T	p.Ala200Ser	missense	Exon 4 of 4	NP_066993.1	Q9HCC6
	HES4	NM_001142467.2		c.676G>T	p.Ala226Ser	missense	Exon 3 of 3	NP_001135939.1	E9PB28
	HES4	NM_001410700.1		c.502G>T	p.Ala168Ser	missense	Exon 3 of 3	NP_001397629.1	D6REB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HES4	ENST00000304952.11	TSL:1 MANE Select	c.598G>T	p.Ala200Ser	missense	Exon 4 of 4	ENSP00000304595.7	Q9HCC6
	HES4	ENST00000428771.6	TSL:2	c.676G>T	p.Ala226Ser	missense	Exon 3 of 3	ENSP00000393198.2	E9PB28
	HES4	ENST00000854802.1		c.538G>T	p.Ala180Ser	missense	Exon 4 of 4	ENSP00000524863.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000563 AC: 6 AN: 1065408 Hom.: 0 Cov.: 29 AF XY: 0.00000596 AC XY: 3 AN XY: 503580

African (AFR) AF: 0.00 AC: 0 AN: 22098

American (AMR) AF: 0.00 AC: 0 AN: 7710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13258

East Asian (EAS) AF: 0.00 AC: 0 AN: 24702

South Asian (SAS) AF: 0.00 AC: 0 AN: 19720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3226

European-Non Finnish (NFE) AF: 0.00000658 AC: 6 AN: 911480

Other (OTH) AF: 0.00 AC: 0 AN: 42298

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.0
DANN	Benign	0.37
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-2.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.010
Sift	Benign	0.56	T
Sift4G	Benign	0.59	T
Polyphen		0.012	B
Vest4		0.078
MutPred		0.17		Gain of glycosylation at A226 (P = 0.0157)
MVP		0.20
MPC		0.53
ClinPred		0.022	T
GERP RS		-2.1
Varity_R		0.033
gMVP		0.34
Mutation Taster		=98/2	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: rs986079419; hg19: chr1-934507;