17-8121707-G-T

Position:

• chr17-8121707-G-T

Variant summary

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

The NM_001165967.2(HES7):​c.557C>A​(p.Ser186Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000749 in 1,201,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: HES7 NM_001165967.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33

Genes affected

HES7 (HGNC:15977): (hes family bHLH transcription factor 7) This gene encodes a member of the hairy and enhancer of split family of bHLH transcription factors. The mouse ortholog of this gene is regulated by Notch signaling. The protein functions as a transcriptional repressor, and is implicated in correct patterning of the axial skeleton. A mutation in this gene has been shown to result in spondylocostal dysostosis. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

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=0.24485162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HES7	NM_001165967.2	c.557C>A	p.Ser186Tyr	missense_variant	4/4	ENST00000541682.7	NP_001159439.1
HES7	NM_032580.4	c.542C>A	p.Ser181Tyr	missense_variant	4/4		NP_115969.2
HES7	XM_047436940.1	c.653C>A	p.Ser218Tyr	missense_variant	3/3		XP_047292896.1
HES7	XM_047436941.1	c.644C>A	p.Ser215Tyr	missense_variant	5/5		XP_047292897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HES7	ENST00000541682.7	c.557C>A	p.Ser186Tyr	missense_variant	4/4	1	NM_001165967.2	ENSP00000446205.2
HES7	ENST00000317814.8	c.542C>A	p.Ser181Tyr	missense_variant	4/4	1		ENSP00000314774.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000749 AC: 9 AN: 1201384 Hom.: 0 Cov.: 30 AF XY: 0.00000516 AC XY: 3 AN XY: 580874

Gnomad4 AFR exome AF: 0.000210

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: 0.00

Gnomad4 OTH exome AF: 0.0000809

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2022

This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 181 of the HES7 protein (p.Ser181Tyr). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with HES7-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.55	.;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.72	.;P
Vest4		0.19
MutPred		0.25		.;Loss of glycosylation at S181 (P = 0.0305);
MVP		0.48
MPC		2.0
ClinPred		0.62	D
GERP RS		3.1
Varity_R		0.069
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

LitVar

Other links and lift over

dbSNP: rs550425522; hg19: chr17-8025025;