1-999090-G-C

Variant names:

• chr1-999090-G-C
• NM_021170.4:c.635C>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.635C>G​(p.Pro212Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,077,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: HES4 NM_021170.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.05

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=0.07113394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HES4	NM_021170.4	c.635C>G	p.Pro212Arg	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.635C>G	p.Pro212Arg	missense_variant	Exon 4 of 4	1	NM_021170.4	ENSP00000304595.7
HES4	ENST00000428771.6	c.713C>G	p.Pro238Arg	missense_variant	Exon 3 of 3	2		ENSP00000393198.2
HES4	ENST00000484667.2	c.539C>G	p.Pro180Arg	missense_variant	Exon 3 of 3	3		ENSP00000425085.1
HES4	ENST00000481869.1	n.914C>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1077684 Hom.: 0 Cov.: 29 AF XY: 0.00000195 AC XY: 1 AN XY: 511590

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000218

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 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.713C>G (p.P238R) 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 713, causing the proline (P) at amino acid position 238 to be replaced by an arginine (R). 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	0.057
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.0020
DANN	Benign	0.52
DEOGEN2	Benign	0.0024	.;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.27	T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.071	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	.;N;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.16	N;N;N
REVEL	Benign	0.058
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.070
MutPred		0.29		Gain of MoRF binding (P = 0.0068);.;.;
MVP		0.23
MPC		0.62
ClinPred		0.098	T
GERP RS		-5.8
Varity_R		0.059
gMVP		0.30

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: chr1-934470;