NM_021170.4:c.605C>G

Variant names:

• chr1-999120-G-C
• rs951940059
• NM_021170.4:c.605C>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.605C>G​(p.Pro202Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000387 in 1,214,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. P202S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: HES4 NM_021170.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.451
• 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=0.06612551).
• BS2: High AC in GnomAd4 at 28 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.605C>G	p.Pro202Arg	missense	Exon 4 of 4	NP_066993.1	Q9HCC6
	HES4	NM_001142467.2		c.683C>G	p.Pro228Arg	missense	Exon 3 of 3	NP_001135939.1	E9PB28
	HES4	NM_001410700.1		c.509C>G	p.Pro170Arg	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.605C>G	p.Pro202Arg	missense	Exon 4 of 4	ENSP00000304595.7	Q9HCC6
	HES4	ENST00000428771.6	TSL:2	c.683C>G	p.Pro228Arg	missense	Exon 3 of 3	ENSP00000393198.2	E9PB28
	HES4	ENST00000854802.1		c.545C>G	p.Pro182Arg	missense	Exon 4 of 4	ENSP00000524863.1

Frequencies

GnomAD3 genomes AF: 0.000185 AC: 28 AN: 151694 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

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: 0.000480

GnomAD4 exome AF: 0.0000179 AC: 19 AN: 1063020 Hom.: 0 Cov.: 29 AF XY: 0.0000239 AC XY: 12 AN XY: 502316

African (AFR) AF: 0.0000453 AC: 1 AN: 22084

American (AMR) AF: 0.000390 AC: 3 AN: 7702

Ashkenazi Jewish (ASJ) AF: 0.000151 AC: 2 AN: 13220

East Asian (EAS) AF: 0.00 AC: 0 AN: 24672

South Asian (SAS) AF: 0.00 AC: 0 AN: 19550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3304

European-Non Finnish (NFE) AF: 0.0000121 AC: 11 AN: 909458

Other (OTH) AF: 0.0000474 AC: 2 AN: 42190

GnomAD4 genome AF: 0.000184 AC: 28 AN: 151802 Hom.: 0 Cov.: 34 AF XY: 0.000175 AC XY: 13 AN XY: 74210

African (AFR) AF: 0.0000241 AC: 1 AN: 41490

American (AMR) AF: 0.00164 AC: 25 AN: 15240

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10416

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67896

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000257

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	0.093
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.81
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.45
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.022
Sift	Benign	0.044	D
Sift4G	Uncertain	0.038	D
Polyphen		0.0050	B
Vest4		0.046
MutPred		0.33		Gain of MoRF binding (P = 5e-04)
MVP		0.34
MPC		0.62
ClinPred		0.057	T
GERP RS		-0.46
Varity_R		0.056
gMVP		0.52
Mutation Taster		=96/4	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: rs951940059; hg19: chr1-934500;