17-8121659-A-G

Variant names:

• chr17-8121659-A-G
• NM_001165967.2:c.605T>C

Variant summary

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

The NM_001165967.2(HES7):​c.605T>C​(p.Leu202Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000599 in 1,169,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000060 (0 hom.)
• Consequence: HES7 NM_001165967.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

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=0.2056458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HES7	NM_001165967.2	c.605T>C	p.Leu202Pro	missense_variant	Exon 4 of 4	ENST00000541682.7	NP_001159439.1
HES7	NM_032580.4	c.590T>C	p.Leu197Pro	missense_variant	Exon 4 of 4		NP_115969.2
HES7	XM_047436940.1	c.701T>C	p.Leu234Pro	missense_variant	Exon 3 of 3		XP_047292896.1
HES7	XM_047436941.1	c.692T>C	p.Leu231Pro	missense_variant	Exon 5 of 5		XP_047292897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HES7	ENST00000541682.7	c.605T>C	p.Leu202Pro	missense_variant	Exon 4 of 4	1	NM_001165967.2	ENSP00000446205.2
HES7	ENST00000317814.8	c.590T>C	p.Leu197Pro	missense_variant	Exon 4 of 4	1		ENSP00000314774.4
HES7	ENST00000577735.1	c.*145T>C		downstream_gene_variant		3		ENSP00000462491.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000599 AC: 7 AN: 1169516 Hom.: 0 Cov.: 30 AF XY: 0.00000712 AC XY: 4 AN XY: 562022

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: 0.0000491

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000513

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 197 of the HES7 protein (p.Leu197Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.13	.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.34	T;T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.34	.;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.67	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D;D
Sift4G	Benign	0.22	T;T
Polyphen		0.0	.;B
Vest4		0.32
MutPred		0.28		.;Gain of glycosylation at L197 (P = 0.0023);
MVP		0.36
MPC		1.7
ClinPred		0.44	T
GERP RS		2.3
Varity_R		0.15
gMVP		0.34

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: chr17-8024977;