1-999364-C-T

Variant names:

• chr1-999364-C-T
• rs759378969
• NM_021170.4:c.361G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_021170.4(HES4):​c.361G>A​(p.Val121Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000334 in 1,347,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: HES4 NM_021170.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.97
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32597744).
• BS2: High AC in GnomAdExome4 at 45 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.361G>A	p.Val121Met	missense	Exon 4 of 4	NP_066993.1	Q9HCC6
	HES4	NM_001142467.2		c.439G>A	p.Val147Met	missense	Exon 3 of 3	NP_001135939.1	E9PB28
	HES4	NM_001410700.1		c.265G>A	p.Val89Met	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.361G>A	p.Val121Met	missense	Exon 4 of 4	ENSP00000304595.7	Q9HCC6
	HES4	ENST00000428771.6	TSL:2	c.439G>A	p.Val147Met	missense	Exon 3 of 3	ENSP00000393198.2	E9PB28
	HES4	ENST00000854802.1		c.301G>A	p.Val101Met	missense	Exon 4 of 4	ENSP00000524863.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000776 AC: 9 AN: 116028 AF XY: 0.000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000334 AC: 45 AN: 1347942 Hom.: 0 Cov.: 30 AF XY: 0.0000525 AC XY: 35 AN XY: 666180

African (AFR) AF: 0.00 AC: 0 AN: 27960

American (AMR) AF: 0.00 AC: 0 AN: 27360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23008

East Asian (EAS) AF: 0.0000633 AC: 2 AN: 31574

South Asian (SAS) AF: 0.000512 AC: 38 AN: 74208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5188

European-Non Finnish (NFE) AF: 0.00000281 AC: 3 AN: 1068164

Other (OTH) AF: 0.0000357 AC: 2 AN: 56004

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000627 AC: 7

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	Pathogenic	0.76
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.094	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.49
MutPred		0.73		Gain of helix (P = 0.0325)
MVP		0.59
MPC		1.6
ClinPred		0.65	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.67
Mutation Taster		=84/16	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: rs759378969; hg19: chr1-934744;