chr17-8123046-C-T

Variant names:

• chr17-8123046-C-T
• rs61731639
• NM_001165967.2:c.123G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001165967.2(HES7):​c.123G>A​(p.Glu41Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0607 in 1,600,464 control chromosomes in the GnomAD database, including 9,287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (1009 hom., cov: 32)
  • Exomes 𝑓: 0.060 (8278 hom.)
• Consequence: HES7 NM_001165967.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.748
• Publications: 10 publications found

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]

HES7 Gene-Disease associations (from GenCC):

• spondylocostal dysostosis 4, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 17-8123046-C-T is Benign according to our data. Variant chr17-8123046-C-T is described in ClinVar as Benign. ClinVar VariationId is 262087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165967.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HES7	NM_001165967.2	MANE Select	c.123G>A	p.Glu41Glu	synonymous	Exon 2 of 4	NP_001159439.1
	HES7	NM_032580.4		c.123G>A	p.Glu41Glu	synonymous	Exon 2 of 4	NP_115969.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HES7	ENST00000541682.7	TSL:1 MANE Select	c.123G>A	p.Glu41Glu	synonymous	Exon 2 of 4	ENSP00000446205.2
	HES7	ENST00000317814.8	TSL:1	c.123G>A	p.Glu41Glu	synonymous	Exon 2 of 4	ENSP00000314774.4
	HES7	ENST00000577735.1	TSL:3	c.99G>A	p.Glu33Glu	synonymous	Exon 3 of 5	ENSP00000462491.1

Frequencies

GnomAD3 genomes AF: 0.0664 AC: 10093 AN: 152094 Hom.: 998 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.0858

Gnomad FIN AF: 0.0506

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0389

Gnomad OTH AF: 0.0814

GnomAD2 exomes AF: 0.119 AC: 26489 AN: 221932 AF XY: 0.106

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.379

Gnomad ASJ exome AF: 0.0855

Gnomad EAS exome AF: 0.374

Gnomad FIN exome AF: 0.0552

Gnomad NFE exome AF: 0.0366

Gnomad OTH exome AF: 0.0965

GnomAD4 exome AF: 0.0600 AC: 86958 AN: 1448252 Hom.: 8278 Cov.: 31 AF XY: 0.0593 AC XY: 42695 AN XY: 719442

African (AFR) AF: 0.0121 AC: 401 AN: 33214

American (AMR) AF: 0.359 AC: 15405 AN: 42862

Ashkenazi Jewish (ASJ) AF: 0.0880 AC: 2270 AN: 25788

East Asian (EAS) AF: 0.430 AC: 16751 AN: 38926

South Asian (SAS) AF: 0.0712 AC: 5994 AN: 84142

European-Finnish (FIN) AF: 0.0512 AC: 2650 AN: 51782

Middle Eastern (MID) AF: 0.0704 AC: 403 AN: 5724

European-Non Finnish (NFE) AF: 0.0352 AC: 38898 AN: 1106010

Other (OTH) AF: 0.0700 AC: 4186 AN: 59804

GnomAD4 genome AF: 0.0665 AC: 10115 AN: 152212 Hom.: 1009 Cov.: 32 AF XY: 0.0723 AC XY: 5380 AN XY: 74398

African (AFR) AF: 0.0127 AC: 528 AN: 41566

American (AMR) AF: 0.232 AC: 3554 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 279 AN: 3472

East Asian (EAS) AF: 0.378 AC: 1940 AN: 5132

South Asian (SAS) AF: 0.0856 AC: 413 AN: 4822

European-Finnish (FIN) AF: 0.0506 AC: 537 AN: 10622

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0389 AC: 2647 AN: 67990

Other (OTH) AF: 0.0853 AC: 180 AN: 2110

Alfa AF: 0.0449 Hom.: 136

Bravo AF: 0.0790

Asia WGS AF: 0.190 AC: 659 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	12
DANN	Benign	0.96
PhyloP100		0.75
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61731639; hg19: chr17-8026364; COSMIC: COSV58555038; COSMIC: COSV58555038;