Genetic Variant SUV39H2:p.Pro15Thr (chr10-14881511-C-A) – 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_001193424.2(SUV39H2):c.43C>A(p.Pro15Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000711 in 1,407,052 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SUV39H2
NM_001193424.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.23

Publications

0 publications found

Variant links:

Genes affected

SUV39H2 (HGNC:17287): (SUV39H2 histone lysine methyltransferase) Enables S-adenosyl-L-methionine binding activity; histone methyltransferase activity (H3-K9 specific); and zinc ion binding activity. Involved in chromatin assembly or disassembly and chromatin remodeling. Acts upstream of or within cellular response to hypoxia and negative regulation of transcription by RNA polymerase II. Located in chromatin. [provided by Alliance of Genome Resources, Apr 2022]

SUV39H2 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
SUV39H2	NM_001193424.2 link	c.43C>A	p.Pro15Thr	missense_variant	Exon 2 of 6	ENST00000354919.11	NP_001180353.1	Q9H5I1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUV39H2	ENST00000354919.11 link	c.43C>A	p.Pro15Thr	missense_variant	Exon 2 of 6	5	NM_001193424.2	ENSP00000346997.6		Q9H5I1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.11e-7

AC:

AN:

1407052

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699062

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30956

American (AMR)

AF:

0.00

AC:

AN:

35388

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24484

East Asian (EAS)

AF:

0.0000271

AC:

AN:

36938

South Asian (SAS)

AF:

0.00

AC:

AN:

75846

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5516

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088930

Other (OTH)

AF:

0.00

AC:

AN:

57804

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.43C>A (p.P15T) alteration is located in exon 2 (coding exon 2) of the SUV39H2 gene. This alteration results from a C to A substitution at nucleotide position 43, causing the proline (P) at amino acid position 15 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;T

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.86

D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.65

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

5.2

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.0

N;N

REVEL

Pathogenic

0.74

Sift

Benign

0.17

T;T

Sift4G

Benign

0.19

T;T

Polyphen

1.0

D;.

Vest4

0.59

MutPred

0.61

Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);

MVP

0.87

MPC

2.2

ClinPred

0.80

GERP RS

5.9

PromoterAI

-0.0025

Neutral

(source)

Varity_R

0.16

gMVP

0.68

Mutation Taster

=34/66

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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10-14881511-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over