1-999087-C-G

Variant names:

• chr1-999087-C-G
• rs778942342
• NM_021170.4:c.638G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021170.4(HES4):​c.638G>C​(p.Gly213Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,084,636 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. 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. G213S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: HES4 NM_021170.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0880
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06428027).

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.638G>C	p.Gly213Ala	missense	Exon 4 of 4	NP_066993.1	Q9HCC6
	HES4	NM_001142467.2		c.716G>C	p.Gly239Ala	missense	Exon 3 of 3	NP_001135939.1	E9PB28
	HES4	NM_001410700.1		c.542G>C	p.Gly181Ala	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.638G>C	p.Gly213Ala	missense	Exon 4 of 4	ENSP00000304595.7	Q9HCC6
	HES4	ENST00000428771.6	TSL:2	c.716G>C	p.Gly239Ala	missense	Exon 3 of 3	ENSP00000393198.2	E9PB28
	HES4	ENST00000854802.1		c.578G>C	p.Gly193Ala	missense	Exon 4 of 4	ENSP00000524863.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1084636 Hom.: 0 Cov.: 29 AF XY: 0.00000194 AC XY: 1 AN XY: 515728

African (AFR) AF: 0.0000877 AC: 2 AN: 22804

American (AMR) AF: 0.00 AC: 0 AN: 10324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13386

East Asian (EAS) AF: 0.00 AC: 0 AN: 25910

South Asian (SAS) AF: 0.00 AC: 0 AN: 21520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3854

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 921820

Other (OTH) AF: 0.00 AC: 0 AN: 42956

GnomAD4 genome Cov.: 34

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	0.066
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.7
DANN	Benign	0.45
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.088
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.0070
Sift	Benign	0.24	T
Sift4G	Benign	0.33	T
Polyphen		0.0010	B
Vest4		0.070
MutPred		0.24		Loss of catalytic residue at P235 (P = 0.0722)
MVP		0.27
MPC		0.63
ClinPred		0.066	T
GERP RS		0.75
Varity_R		0.039
gMVP		0.48
Mutation Taster		=97/3	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: rs778942342; hg19: chr1-934467;