17-8121582-G-C

Variant names:

• chr17-8121582-G-C
• NM_001165967.2:c.682C>G

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 rank	MANE	Protein	UniProt
HES7	NM_001165967.2	c.682C>G	p.Pro228Ala	missense_variant	Exon 4 of 4	ENST00000541682.7	NP_001159439.1
HES7	NM_032580.4	c.667C>G	p.Pro223Ala	missense_variant	Exon 4 of 4		NP_115969.2
HES7	XM_047436940.1	c.778C>G	p.Pro260Ala	missense_variant	Exon 3 of 3		XP_047292896.1
HES7	XM_047436941.1	c.769C>G	p.Pro257Ala	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.682C>G	p.Pro228Ala	missense_variant	Exon 4 of 4	1	NM_001165967.2	ENSP00000446205.2
HES7	ENST00000317814.8	c.667C>G	p.Pro223Ala	missense_variant	Exon 4 of 4	1		ENSP00000314774.4
HES7	ENST00000577735.1	c.*222C>G		downstream_gene_variant		3		ENSP00000462491.1

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

Mar 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;