17-8121686-C-T

Position:

• chr17-8121686-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001165967.2(HES7):​c.578G>A​(p.Gly193Asp) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G193S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HES7 NM_001165967.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58

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 3 ACMG points.

• PM1: In a chain Transcription factor HES-7 (size 224) in uniprot entity HES7_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001165967.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31250602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HES7	NM_001165967.2	c.578G>A	p.Gly193Asp	missense_variant	4/4	ENST00000541682.7
HES7	NM_032580.4	c.563G>A	p.Gly188Asp	missense_variant	4/4
HES7	XM_047436940.1	c.674G>A	p.Gly225Asp	missense_variant	3/3
HES7	XM_047436941.1	c.665G>A	p.Gly222Asp	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HES7	ENST00000541682.7	c.578G>A	p.Gly193Asp	missense_variant	4/4	1	NM_001165967.2	A1
HES7	ENST00000317814.8	c.563G>A	p.Gly188Asp	missense_variant	4/4	1		P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.00088	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.53	T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.69	.;N
MutationTaster	Benign	0.64	N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.28
Sift	Benign	0.22	T;T
Sift4G	Uncertain	0.039	D;D
Polyphen		0.96	.;D
Vest4		0.21
MutPred		0.22		.;Gain of loop (P = 0.0435);
MVP		0.58
MPC		2.1
ClinPred		0.82	D
GERP RS		4.1
Varity_R		0.14
gMVP		0.21

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: rs1981333577; hg19: chr17-8025004;