1-999289-A-C

Variant names:

• chr1-999289-A-C
• NM_021170.4:c.436T>G

Variant summary

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

The NM_021170.4(HES4):​c.436T>G​(p.Cys146Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 2.40

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HES4	NM_021170.4	c.436T>G	p.Cys146Gly	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.436T>G	p.Cys146Gly	missense_variant	Exon 4 of 4	1	NM_021170.4	ENSP00000304595.7
HES4	ENST00000428771.6	c.514T>G	p.Cys172Gly	missense_variant	Exon 3 of 3	2		ENSP00000393198.2
HES4	ENST00000484667.2	c.340T>G	p.Cys114Gly	missense_variant	Exon 3 of 3	3		ENSP00000425085.1
HES4	ENST00000481869.1	n.715T>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.514T>G (p.C172G) alteration is located in exon 3 (coding exon 3) of the HES4 gene. This alteration results from a T to G substitution at nucleotide position 514, causing the cysteine (C) at amino acid position 172 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	0.14
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.11	.;T;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.68	T;T;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.4	.;M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-9.4	D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.42	B;D;.
Vest4		0.39
MutPred		0.66		Loss of stability (P = 0.0123);.;.;
MVP		0.46
MPC		1.6
ClinPred		1.0	D
GERP RS		0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.67
gMVP		0.51

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: chr1-934669;