Genetic Variant PRDM13:p.Lys35Asn (chr6-99607139-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_021620.4(PRDM13):c.105G>C(p.Lys35Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,596 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. Synonymous variant affecting the same amino acid position (i.e. K35K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRDM13
NM_021620.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.57

Publications

0 publications found

Variant links:

Genes affected

PRDM13 (HGNC:13998): (PR/SET domain 13) Predicted to enable RNA polymerase II-specific DNA-binding transcription factor binding activity; chromatin binding activity; and histone methyltransferase activity. Predicted to be involved in regulation of gene expression. Predicted to act upstream of or within negative regulation of transcription by RNA polymerase II and neurogenesis. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

PRDM13 Gene-Disease associations (from GenCC):

North Carolina macular dystrophy
Inheritance: AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Franklin by Genoox, G2P, Ambry Genetics
pontocerebellar hypoplasia, IIA 17
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

PRDM13 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33772066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM13	NM_021620.4 link	c.105G>C	p.Lys35Asn	missense_variant	Exon 1 of 4	ENST00000369215.5	NP_067633.2	Q9H4Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM13	ENST00000369215.5 link	c.105G>C	p.Lys35Asn	missense_variant	Exon 1 of 4	1	NM_021620.4	ENSP00000358217.5		Q9H4Q3
PRDM13	ENST00000369214.2 link	n.105G>C		non_coding_transcript_exon_variant	Exon 1 of 4	5		ENSP00000358216.2		A0A0A0MRL5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461596

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111984

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Pathogenic

0.95

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.018

MetaRNN

Benign

0.34

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.1

PhyloP100

3.6

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.19

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.40

MutPred

0.25

Loss of methylation at K35 (P = 0.0094);

MVP

0.29

ClinPred

0.98

GERP RS

4.1

PromoterAI

-0.034

Neutral

(source)

Varity_R

0.50

gMVP

0.59

Mutation Taster

=57/43

polymorphism

(source)

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

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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