17-8121668-G-A

Position:

• chr17-8121668-G-A

Variant summary

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

The NM_001165967.2(HES7):​c.596C>T​(p.Thr199Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000226 in 1,329,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: HES7 NM_001165967.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:1
• Conservation: PhyloP100: 2.70

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=0.3648708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HES7	NM_001165967.2	c.596C>T	p.Thr199Ile	missense_variant	4/4	ENST00000541682.7
HES7	NM_032580.4	c.581C>T	p.Thr194Ile	missense_variant	4/4
HES7	XM_047436940.1	c.692C>T	p.Thr231Ile	missense_variant	3/3
HES7	XM_047436941.1	c.683C>T	p.Thr228Ile	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HES7	ENST00000541682.7	c.596C>T	p.Thr199Ile	missense_variant	4/4	1	NM_001165967.2	A1
HES7	ENST00000317814.8	c.581C>T	p.Thr194Ile	missense_variant	4/4	1		P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000170 AC: 2 AN: 1177426 Hom.: 0 Cov.: 30 AF XY: 0.00000353 AC XY: 2 AN XY: 566126

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: 0.00

Gnomad4 OTH exome AF: 0.0000412

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 30, 2021

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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces threonine with isoleucine at codon 194 of the HES7 protein (p.Thr194Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.44	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.69	.;N
MutationTaster	Benign	0.99	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.24
Sift	Benign	0.20	T;T
Sift4G	Benign	0.42	T;T
Polyphen		1.0	.;D
Vest4		0.22
MutPred		0.26		.;Loss of phosphorylation at T194 (P = 0.0059);
MVP		0.52
MPC		1.9
ClinPred		0.88	D
GERP RS		5.1
Varity_R		0.071
gMVP		0.58

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: rs1365151656; hg19: chr17-8024986;