dbSNP rs535914789: HES7:c.*12T>G (chr17-8121559-A-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001165967.2(HES7):c.*12T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000505 in 1,292,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

HES7
NM_001165967.2 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0900

Publications

0 publications found

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 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

HES7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00143 (216/151034) while in subpopulation AFR AF = 0.00438 (180/41084). AF 95% confidence interval is 0.00386. There are 0 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HES7	NM_001165967.2	MANE Select	c.*12T>G		3_prime_UTR	Exon 4 of 4	NP_001159439.1	Q9BYE0-2
	HES7	NM_032580.4		c.*12T>G		3_prime_UTR	Exon 4 of 4	NP_115969.2	Q9BYE0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HES7	ENST00000541682.7	TSL:1 MANE Select	c.*12T>G	3_prime_UTR	Exon 4 of 4	ENSP00000446205.2	Q9BYE0-2
HES7	ENST00000317814.8	TSL:1	c.*12T>G	downstream_gene	N/A	ENSP00000314774.4	Q9BYE0-1
HES7	ENST00000577735.1	TSL:3	c.*245T>G	downstream_gene	N/A	ENSP00000462491.1	J3KSH6

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

216

AN:

150930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00439

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000722

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000632

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000310

Gnomad OTH

AF:

0.000483

GnomAD2 exomes

AF:

0.00495

AC:

AN:

202

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.167

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000382

AC:

436

AN:

1141320

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

219

AN XY:

543490

show subpopulations

African (AFR)

AF:

0.00513

AC:

119

AN:

23180

American (AMR)

AF:

0.000460

AC:

AN:

8690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15672

East Asian (EAS)

AF:

0.00

AC:

AN:

26716

South Asian (SAS)

AF:

0.000243

AC:

AN:

32928

European-Finnish (FIN)

AF:

0.0000396

AC:

AN:

25242

Middle Eastern (MID)

AF:

0.000316

AC:

AN:

3162

European-Non Finnish (NFE)

AF:

0.000299

AC:

287

AN:

958726

Other (OTH)

AF:

0.000340

AC:

AN:

47004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00143

AC:

216

AN:

151034

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

73772

show subpopulations

African (AFR)

AF:

0.00438

AC:

180

AN:

41084

American (AMR)

AF:

0.000721

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.000633

AC:

AN:

4740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000310

AC:

AN:

67658

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000713

Hom.:

Bravo

AF:

0.00167

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

4.0

(source)

DANN

Benign

0.30

PhyloP100

-0.090

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over