chr17-8121668-G-C

Variant names:

• chr17-8121668-G-C
• rs1365151656
• NM_001165967.2:c.596C>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS1

The NM_001165967.2(HES7):​c.596C>G​(p.Thr199Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,329,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: HES7 NM_001165967.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.70

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19802865).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000161 (19/1177426) while in subpopulation EAS AF= 0.000704 (19/26996). AF 95% confidence interval is 0.00046. There are 0 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HES7	NM_001165967.2	c.596C>G	p.Thr199Ser	missense_variant	Exon 4 of 4	ENST00000541682.7	NP_001159439.1
HES7	NM_032580.4	c.581C>G	p.Thr194Ser	missense_variant	Exon 4 of 4		NP_115969.2
HES7	XM_047436940.1	c.692C>G	p.Thr231Ser	missense_variant	Exon 3 of 3		XP_047292896.1
HES7	XM_047436941.1	c.683C>G	p.Thr228Ser	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.596C>G	p.Thr199Ser	missense_variant	Exon 4 of 4	1	NM_001165967.2	ENSP00000446205.2
HES7	ENST00000317814.8	c.581C>G	p.Thr194Ser	missense_variant	Exon 4 of 4	1		ENSP00000314774.4
HES7	ENST00000577735.1	c.*136C>G		downstream_gene_variant		3		ENSP00000462491.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000161 AC: 19 AN: 1177426 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 7 AN XY: 566126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000704

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.36	T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.69	.;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.23	N;N
REVEL	Benign	0.22
Sift	Benign	0.85	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.38	.;B
Vest4		0.10
MutPred		0.16		.;Gain of glycosylation at T194 (P = 0.0169);
MVP		0.63
MPC		1.7
ClinPred		0.51	D
GERP RS		5.1
Varity_R		0.072
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1365151656; hg19: chr17-8024986;