1-999105-G-C

Variant names:

• chr1-999105-G-C
• NM_021170.4:c.620C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021170.4(HES4):​c.620C>G​(p.Ala207Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: HES4 NM_021170.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.380

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11028579).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HES4	NM_021170.4	c.620C>G	p.Ala207Gly	missense_variant	Exon 4 of 4	ENST00000304952.11	NP_066993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HES4	ENST00000304952.11	c.620C>G	p.Ala207Gly	missense_variant	Exon 4 of 4	1	NM_021170.4	ENSP00000304595.7
HES4	ENST00000428771.6	c.698C>G	p.Ala233Gly	missense_variant	Exon 3 of 3	2		ENSP00000393198.2
HES4	ENST00000484667.2	c.524C>G	p.Ala175Gly	missense_variant	Exon 3 of 3	3		ENSP00000425085.1
HES4	ENST00000481869.1	n.899C>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.698C>G (p.A233G) alteration is located in exon 3 (coding exon 3) of the HES4 gene. This alteration results from a C to G substitution at nucleotide position 698, causing the alanine (A) at amino acid position 233 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.0097	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.48	T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;N;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.89	N;N;N
REVEL	Benign	0.011
Sift	Benign	0.069	T;T;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.054	B;B;.
Vest4		0.12
MutPred		0.17		Gain of methylation at R232 (P = 0.0801);.;.;
MVP		0.24
MPC		0.59
ClinPred		0.080	T
GERP RS		0.43
Varity_R		0.048
gMVP		0.42

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-934485;