17-8121673-G-A

Position:

• chr17-8121673-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001165967.2(HES7):​c.591C>T​(p.Pro197=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,327,368 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (5 hom.)
• Consequence: HES7 NM_001165967.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.781

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 17-8121673-G-A is Benign according to our data. Variant chr17-8121673-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288808.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=0.781 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00329 (501/152190) while in subpopulation AFR AF= 0.00773 (321/41544). AF 95% confidence interval is 0.00703. There are 3 homozygotes in gnomad4. There are 242 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HES7	NM_001165967.2	c.591C>T	p.Pro197=	synonymous_variant	4/4	ENST00000541682.7
HES7	NM_032580.4	c.576C>T	p.Pro192=	synonymous_variant	4/4
HES7	XM_047436940.1	c.687C>T	p.Pro229=	synonymous_variant	3/3
HES7	XM_047436941.1	c.678C>T	p.Pro226=	synonymous_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HES7	ENST00000541682.7	c.591C>T	p.Pro197=	synonymous_variant	4/4	1	NM_001165967.2	A1
HES7	ENST00000317814.8	c.576C>T	p.Pro192=	synonymous_variant	4/4	1		P4

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 501 AN: 152082 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.000693 AC: 1 AN: 1444 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000939 AC: 1104 AN: 1175178 Hom.: 5 Cov.: 30 AF XY: 0.000910 AC XY: 514 AN XY: 564664

Gnomad4 AFR exome AF: 0.00821

Gnomad4 AMR exome AF: 0.00613

Gnomad4 ASJ exome AF: 0.00298

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000367

Gnomad4 NFE exome AF: 0.000651

Gnomad4 OTH exome AF: 0.00273

GnomAD4 genome AF: 0.00329 AC: 501 AN: 152190 Hom.: 3 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74414

Gnomad4 AFR AF: 0.00773

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00228 Hom.: 1

Bravo AF: 0.00476

Asia WGS AF: 0.000871 AC: 3 AN: 3460

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 28, 2016	- -

HES7-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.96

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: rs558811781; hg19: chr17-8024991;