Genetic Variant HES7:p.Arg227Ser (chr17-8121583-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001165967.2(HES7):c.681A>C(p.Arg227Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000305 in 1,309,760 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000026 ( 0 hom. )

Consequence

HES7
NM_001165967.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.259

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 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 link	c.681A>C	p.Arg227Ser	missense_variant	Exon 4 of 4	ENST00000541682.7	NP_001159439.1	Q9BYE0-2
HES7	NM_032580.4 link	c.666A>C	p.Arg222Ser	missense_variant	Exon 4 of 4		NP_115969.2	Q9BYE0-1
HES7	XM_047436940.1 link	c.777A>C	p.Arg259Ser	missense_variant	Exon 3 of 3		XP_047292896.1
HES7	XM_047436941.1 link	c.768A>C	p.Arg256Ser	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.681A>C	p.Arg227Ser	missense_variant	Exon 4 of 4	1	NM_001165967.2	ENSP00000446205.2	Q9BYE0-2
HES7	ENST00000317814.8 link	c.666A>C	p.Arg222Ser	missense_variant	Exon 4 of 4	1		ENSP00000314774.4	Q9BYE0-1
HES7	ENST00000577735.1 link	c.*221A>C		downstream_gene_variant		3		ENSP00000462491.1	J3KSH6

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151810

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:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000259

AC:

AN:

1157842

Hom.:

Cov.:

AF XY:

0.00000180

AC XY:

AN XY:

554370

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000800

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151918

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

.;D

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.091

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.55

T;T

M_CAP

Pathogenic

0.88

MetaRNN

Uncertain

0.66

D;D

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.81

.;L

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-4.1

D;D

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.14

.;B

Vest4

0.63

MutPred

0.48

.;Gain of glycosylation at R222 (P = 0.0093);

MVP

0.99

MPC

0.83

ClinPred

0.92

GERP RS

4.0

Varity_R

0.82

gMVP

0.65

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

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