1-999365-C-G

Variant names:

• chr1-999365-C-G
• rs567970457
• NM_021170.4:c.360G>C

Variant summary

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

The NM_021170.4(HES4):​c.360G>C​(p.Glu120Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000961 in 1,498,446 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: 𝑓 0.00013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: HES4 NM_021170.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.804
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2678033).
• BS2: High AC in GnomAd4 at 20 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.360G>C	p.Glu120Asp	missense	Exon 4 of 4	NP_066993.1	Q9HCC6
	HES4	NM_001142467.2		c.438G>C	p.Glu146Asp	missense	Exon 3 of 3	NP_001135939.1	E9PB28
	HES4	NM_001410700.1		c.264G>C	p.Glu88Asp	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.360G>C	p.Glu120Asp	missense	Exon 4 of 4	ENSP00000304595.7	Q9HCC6
	HES4	ENST00000428771.6	TSL:2	c.438G>C	p.Glu146Asp	missense	Exon 3 of 3	ENSP00000393198.2	E9PB28
	HES4	ENST00000854802.1		c.300G>C	p.Glu100Asp	missense	Exon 4 of 4	ENSP00000524863.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152176 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000148 AC: 17 AN: 114836 AF XY: 0.0000904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000635

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000897

Gnomad OTH exome AF: 0.000703

GnomAD4 exome AF: 0.0000921 AC: 124 AN: 1346162 Hom.: 0 Cov.: 30 AF XY: 0.0000887 AC XY: 59 AN XY: 665194

African (AFR) AF: 0.00 AC: 0 AN: 27904

American (AMR) AF: 0.000520 AC: 14 AN: 26904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22912

East Asian (EAS) AF: 0.00 AC: 0 AN: 31568

South Asian (SAS) AF: 0.0000676 AC: 5 AN: 73936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5186

European-Non Finnish (NFE) AF: 0.0000937 AC: 100 AN: 1067316

Other (OTH) AF: 0.0000894 AC: 5 AN: 55934

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152284 Hom.: 0 Cov.: 34 AF XY: 0.000161 AC XY: 12 AN XY: 74454

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.000327 AC: 5 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000907

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	0.85
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.061	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.80
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.88	P
Vest4		0.27
MutPred		0.73		Gain of helix (P = 0.0854)
MVP		0.79
MPC		1.5
ClinPred		0.43	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.62
Mutation Taster		=90/10	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: rs567970457; hg19: chr1-934745;