chr17-8121582-G-C

Position:

• chr17-8121582-G-C

Variant summary

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

The NM_001165967.2(HES7):​c.682C>G​(p.Pro228Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000863 in 1,159,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: HES7 NM_001165967.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.40

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HES7	NM_001165967.2	c.682C>G	p.Pro228Ala	missense_variant	4/4	ENST00000541682.7	NP_001159439.1
HES7	NM_032580.4	c.667C>G	p.Pro223Ala	missense_variant	4/4		NP_115969.2
HES7	XM_047436940.1	c.778C>G	p.Pro260Ala	missense_variant	3/3		XP_047292896.1
HES7	XM_047436941.1	c.769C>G	p.Pro257Ala	missense_variant	5/5		XP_047292897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HES7	ENST00000541682.7	c.682C>G	p.Pro228Ala	missense_variant	4/4	1	NM_001165967.2	ENSP00000446205.2
HES7	ENST00000317814.8	c.667C>G	p.Pro223Ala	missense_variant	4/4	1		ENSP00000314774.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.63e-7 AC: 1 AN: 1159008 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 555004

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: 0.00000103

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 03, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 223 of the HES7 protein (p.Pro223Ala). This variant has not been reported in the literature in individuals affected with HES7-related conditions. ClinVar contains an entry for this variant (Variation ID: 1051206). 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: "Not Available"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	.;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.55	T;T
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Uncertain	-0.0025	T
MutationAssessor	Benign	0.81	.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.56
MutPred		0.36		.;Gain of MoRF binding (P = 0.0207);
MVP		0.76
MPC		0.72
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.73
gMVP		0.41

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: chr17-8024900;