Genetic Variant NM_001165967.2:c.596C>G (chr17-8121668-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.70

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 link	c.596C>G	p.Thr199Ser	missense_variant	Exon 4 of 4	ENST00000541682.7	NP_001159439.1	Q9BYE0-2
HES7	NM_032580.4 link	c.581C>G	p.Thr194Ser	missense_variant	Exon 4 of 4		NP_115969.2	Q9BYE0-1
HES7	XM_047436940.1 link	c.692C>G	p.Thr231Ser	missense_variant	Exon 3 of 3		XP_047292896.1
HES7	XM_047436941.1 link	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	UniProt
HES7	ENST00000541682.7 link	c.596C>G	p.Thr199Ser	missense_variant	Exon 4 of 4	1	NM_001165967.2	ENSP00000446205.2	Q9BYE0-2
HES7	ENST00000317814.8 link	c.581C>G	p.Thr194Ser	missense_variant	Exon 4 of 4	1		ENSP00000314774.4	Q9BYE0-1
HES7	ENST00000577735.1 link	c.*136C>G		downstream_gene_variant		3		ENSP00000462491.1	J3KSH6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

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:

AN:

1177426

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

566126

show subpopulations

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:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

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

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

.;T

Eigen

Benign

-0.12

Eigen_PC

Benign

0.036

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.36

T;T

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.69

.;N

PrimateAI

Pathogenic

0.89

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over