Genetic Variant SUZ12:p.His6Tyr (chr17-31937262-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015355.4(SUZ12):c.16C>T(p.His6Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000804 in 1,244,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H6D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

SUZ12
NM_015355.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.38

Publications

0 publications found

Variant links:

Genes affected

SUZ12 (HGNC:17101): (SUZ12 polycomb repressive complex 2 subunit) This zinc finger gene has been identified at the breakpoints of a recurrent chromosomal translocation reported in endometrial stromal sarcoma. Recombination of these breakpoints results in the fusion of this gene and JAZF1. The protein encoded by this gene contains a zinc finger domain in the C terminus of the coding region. [provided by RefSeq, Jul 2009]

SUZ12 Gene-Disease associations (from GenCC):

Imagawa-Matsumoto syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
Weaver syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SUZ12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
SUZ12	NM_015355.4 link	c.16C>T	p.His6Tyr	missense_variant	Exon 1 of 16	ENST00000322652.10	NP_056170.2	Q15022

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUZ12	ENST00000322652.10 link	c.16C>T	p.His6Tyr	missense_variant	Exon 1 of 16	1	NM_015355.4	ENSP00000316578.5		Q15022
SUZ12	ENST00000580398.2 link	c.16C>T	p.His6Tyr	missense_variant	Exon 1 of 15	1		ENSP00000463936.1		J3QQW9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.04e-7

AC:

AN:

1244220

Hom.:

Cov.:

AF XY:

0.00000164

AC XY:

AN XY:

608770

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23830

American (AMR)

AF:

0.00

AC:

AN:

9994

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19182

East Asian (EAS)

AF:

0.00

AC:

AN:

27792

South Asian (SAS)

AF:

0.00

AC:

AN:

58422

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3576

European-Non Finnish (NFE)

AF:

9.82e-7

AC:

AN:

1018250

Other (OTH)

AF:

0.00

AC:

AN:

51492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.095

T;T

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.72

T;T

M_CAP

Pathogenic

0.86

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.1

L;.

PhyloP100

3.4

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.27

Sift

Uncertain

0.024

D;.

Sift4G

Uncertain

0.042

D;D

Polyphen

0.82

P;.

Vest4

0.37

MutPred

0.20

Gain of phosphorylation at H6 (P = 0.03);Gain of phosphorylation at H6 (P = 0.03);

MVP

0.54

MPC

1.1

ClinPred

0.85

GERP RS

4.5

PromoterAI

0.018

Neutral

(source)

Varity_R

0.26

gMVP

0.17

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: -2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over