17-31937319-T-C

Variant names:

• chr17-31937319-T-C
• rs1161554779
• NM_015355.4:c.73T>C

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.73T>C​(p.Phe25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,654 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 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: SUZ12 NM_015355.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.36
• 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=0.21020919).

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.73T>C	p.Phe25Leu	missense	Exon 1 of 16	NP_056170.2	Q15022
	SUZ12	NM_001321207.2		c.73T>C	p.Phe25Leu	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.73T>C	p.Phe25Leu	missense	Exon 1 of 16	ENSP00000316578.5	Q15022
	SUZ12	ENST00000580398.2	TSL:1	c.73T>C	p.Phe25Leu	missense	Exon 1 of 15	ENSP00000463936.1	J3QQW9
	SUZ12	ENST00000934319.1		c.73T>C	p.Phe25Leu	missense	Exon 1 of 17	ENSP00000604378.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151482 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000243

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.67e-7 AC: 1 AN: 1303172 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 639656

African (AFR) AF: 0.00 AC: 0 AN: 25968

American (AMR) AF: 0.00 AC: 0 AN: 22670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20778

East Asian (EAS) AF: 0.00 AC: 0 AN: 29162

South Asian (SAS) AF: 0.00 AC: 0 AN: 67878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3776

European-Non Finnish (NFE) AF: 9.58e-7 AC: 1 AN: 1043314

Other (OTH) AF: 0.00 AC: 0 AN: 54100

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151482 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 73930

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

African (AFR) AF: 0.0000243 AC: 1 AN: 41222

American (AMR) AF: 0.00 AC: 0 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67836

Other (OTH) AF: 0.00 AC: 0 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.0073
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.19
Sift	Benign	0.45	T
Sift4G	Benign	0.095	T
Polyphen		0.23	B
Vest4		0.32
MutPred		0.20		Gain of helix (P = 0.2684)
MVP		0.63
MPC		1.1
ClinPred		0.68	D
GERP RS		4.7
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0
Varity_R		0.33
gMVP		0.21
Mutation Taster		=79/21	polymorphism

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: rs1161554779; hg19: chr17-30264338;