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: Uncertain significance criteria provided, single submitter U:1
• 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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2024

The c.563G>A (p.G188D) alteration is located in exon 4 (coding exon 4) of the HES7 gene. This alteration results from a G to A substitution at nucleotide position 563, causing the glycine (G) at amino acid position 188 to be replaced by an aspartic acid (D). 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	0.13
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;