17-31937335-C-T

Variant names:

• chr17-31937335-C-T
• rs1284405136
• NM_015355.4:c.89C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015355.4(SUZ12):​c.89C>T​(p.Ala30Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000034 in 1,470,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: SUZ12 NM_015355.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33
• Publications: 0 publications found

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, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, PanelApp Australia
• Weaver syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19765282).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015355.4. 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
	SUZ12	NM_015355.4	MANE Select	c.89C>T	p.Ala30Val	missense	Exon 1 of 16	NP_056170.2	Q15022
	SUZ12	NM_001321207.2		c.89C>T	p.Ala30Val	missense	Exon 1 of 15	NP_001308136.1	J3QQW9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUZ12	ENST00000322652.10	TSL:1 MANE Select	c.89C>T	p.Ala30Val	missense	Exon 1 of 16	ENSP00000316578.5	Q15022
	SUZ12	ENST00000580398.2	TSL:1	c.89C>T	p.Ala30Val	missense	Exon 1 of 15	ENSP00000463936.1	J3QQW9
	SUZ12	ENST00000934319.1		c.89C>T	p.Ala30Val	missense	Exon 1 of 17	ENSP00000604378.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151878 Hom.: 0 Cov.: 30

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: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000303 AC: 4 AN: 1318610 Hom.: 0 Cov.: 31 AF XY: 0.00000308 AC XY: 2 AN XY: 648546

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26326

American (AMR) AF: 0.0000411 AC: 1 AN: 24350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21910

East Asian (EAS) AF: 0.00 AC: 0 AN: 29176

South Asian (SAS) AF: 0.00 AC: 0 AN: 70882

European-Finnish (FIN) AF: 0.0000258 AC: 1 AN: 38800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3840

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1048662

Other (OTH) AF: 0.00 AC: 0 AN: 54664

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0843343), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151878 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74164

African (AFR) AF: 0.00 AC: 0 AN: 41350

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.13
Sift	Benign	0.17	T
Sift4G	Uncertain	0.011	D
Polyphen		0.0040	B
Vest4		0.23
MutPred		0.26		Loss of helix (P = 0.0138)
MVP		0.32
MPC		0.92
ClinPred		0.88	D
GERP RS		3.4
PromoterAI		-0.0080	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4
Varity_R		0.078
gMVP		0.26

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

Other links and lift over

dbSNP: rs1284405136; hg19: chr17-30264354;