4-80200097-T-A

Position:

• chr4-80200097-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099403.2(PRDM8):​c.17T>A​(p.Ile6Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

Genes affected

PRDM8 (HGNC:13993): (PR/SET domain 8) This gene encodes a protein that belongs to a conserved family of histone methyltransferases that predominantly act as negative regulators of transcription. The encoded protein contains an N-terminal Su(var)3-9, Enhancer-of-zeste, and Trithorax (SET) domain and a double zinc-finger domain. Knockout of this gene in mouse results in mistargeting by neurons of the dorsal telencephalon, abnormal itch-like behavior, and impaired differentiation of rod bipolar cells. In humans, the protein has been shown to interact with the phosphatase laforin and the ubiquitin ligase malin, which regulate glycogen construction in the cytoplasm. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24089688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM8	NM_001099403.2	c.17T>A	p.Ile6Asn	missense_variant	2/4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.17T>A	p.Ile6Asn	missense_variant	8/10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.17T>A	p.Ile6Asn	missense_variant	2/4	1	NM_001099403.2	ENSP00000406998	P1
PRDM8	ENST00000339711.8	c.17T>A	p.Ile6Asn	missense_variant	8/10	1		ENSP00000339764	P1
PRDM8	ENST00000515013.5	c.17T>A	p.Ile6Asn	missense_variant	8/10	1		ENSP00000425149
PRDM8	ENST00000504452.5	c.17T>A	p.Ile6Asn	missense_variant	6/8	5		ENSP00000423985	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early-onset Lafora body disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.039	T;.;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	.;T;T;.
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.69	N;.;N;N
MutationTaster	Benign	0.89	N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.61	P;.;P;P
Vest4		0.52
MutPred		0.32		Gain of disorder (P = 0.0212);Gain of disorder (P = 0.0212);Gain of disorder (P = 0.0212);Gain of disorder (P = 0.0212);
MVP		0.68
ClinPred		0.84	D
GERP RS		5.4
Varity_R		0.51
gMVP		0.53

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: rs1738314211; hg19: chr4-81121251;