rs1131692177

Positions:

• chr17-31996832-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_015355.4(SUZ12):​c.1829A>T​(p.Glu610Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SUZ12 NM_015355.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a region_of_interest VEFS-box (size 76) in uniprot entity SUZ12_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_015355.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SUZ12. . Gene score misZ 3.4007 (greater than the threshold 3.09). Trascript score misZ 4.0119 (greater than threshold 3.09). GenCC has associacion of gene with Imagawa-Matsumoto syndrome, Weaver syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 17-31996832-A-T is Pathogenic according to our data. Variant chr17-31996832-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 430647.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-31996832-A-T is described in Lovd as [Likely_pathogenic]. Variant chr17-31996832-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUZ12	NM_015355.4	c.1829A>T	p.Glu610Val	missense_variant	15/16	ENST00000322652.10	NP_056170.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUZ12	ENST00000322652.10	c.1829A>T	p.Glu610Val	missense_variant	15/16	1	NM_015355.4	ENSP00000316578	P1
SUZ12	ENST00000580398.1	c.1760A>T	p.Glu587Val	missense_variant	14/15	1		ENSP00000463936
SUZ12	ENST00000578106.1	n.603A>T		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Imagawa-Matsumoto syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	31
DANN	Benign	0.96
DEOGEN2	Uncertain	0.69	D;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.3	D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.89		Loss of disorder (P = 0.021);.;
MVP		0.93
MPC		3.5
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.97

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

Other links and lift over

dbSNP: rs1131692177; hg19: chr17-30323851;