1-999595-G-C

Variant names:

• chr1-999595-G-C
• rs746094252
• NM_021170.4:c.223C>G

Variant summary

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

The NM_021170.4(HES4):​c.223C>G​(p.Leu75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,457,248 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HES4 NM_021170.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

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.223C>G	p.Leu75Val	missense_variant	Exon 3 of 4	ENST00000304952.11	NP_066993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HES4	ENST00000304952.11	c.223C>G	p.Leu75Val	missense_variant	Exon 3 of 4	1	NM_021170.4	ENSP00000304595.7
HES4	ENST00000428771.6	c.301C>G	p.Leu101Val	missense_variant	Exon 2 of 3	2		ENSP00000393198.2
HES4	ENST00000484667.2	c.127C>G	p.Leu43Val	missense_variant	Exon 2 of 3	3		ENSP00000425085.1
HES4	ENST00000481869.1	n.502C>G		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000825 AC: 2 AN: 242352 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000569

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000911

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1457248 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.301C>G (p.L101V) alteration is located in exon 2 (coding exon 2) of the HES4 gene. This alteration results from a C to G substitution at nucleotide position 301, causing the leucine (L) at amino acid position 101 to be replaced by a valine (V). 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	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	.;D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	.;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.33
MutPred		0.70		Gain of methylation at K100 (P = 0.0357);.;.;
MVP		0.77
MPC		1.6
ClinPred		0.95	D
GERP RS		2.3
Varity_R		0.58
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746094252; hg19: chr1-934975;