NM_001099403.2:c.543A>T

Variant names:

• chr4-80202005-A-T
• rs377755509
• NM_001099403.2:c.543A>T

Variant summary

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

The NM_001099403.2(PRDM8):​c.543A>T​(p.Arg181Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PRDM8 NM_001099403.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52

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 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
PRDM8	NM_001099403.2	c.543A>T	p.Arg181Ser	missense_variant	Exon 4 of 4	ENST00000415738.3	NP_001092873.1
PRDM8	NM_020226.4	c.543A>T	p.Arg181Ser	missense_variant	Exon 10 of 10		NP_064611.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM8	ENST00000415738.3	c.543A>T	p.Arg181Ser	missense_variant	Exon 4 of 4	1	NM_001099403.2	ENSP00000406998.2
PRDM8	ENST00000339711.8	c.543A>T	p.Arg181Ser	missense_variant	Exon 10 of 10	1		ENSP00000339764.4
PRDM8	ENST00000515013.5	c.543A>T	p.Arg181Ser	missense_variant	Exon 10 of 10	1		ENSP00000425149.1
PRDM8	ENST00000504452.5	c.543A>T	p.Arg181Ser	missense_variant	Exon 8 of 8	5		ENSP00000423985.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151770 Hom.: 0 Cov.: 31

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461882 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151770 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74088

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early-onset Lafora body disease Uncertain:1

Jan 27, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PRDM8-related disease. This variant is present in population databases (rs377755509, ExAC 0.002%). This sequence change replaces arginine with serine at codon 181 of the PRDM8 protein (p.Arg181Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;T;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	.;T;T;.
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	2.0	M;.;M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	D;N;D;D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;T;D;D
Sift4G	Benign	0.096	T;D;T;T
Polyphen		1.0	D;.;D;D
Vest4		0.77
MutPred		0.46		Loss of catalytic residue at R181 (P = 0.0218);Loss of catalytic residue at R181 (P = 0.0218);Loss of catalytic residue at R181 (P = 0.0218);Loss of catalytic residue at R181 (P = 0.0218);
MVP		0.81
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.65
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs377755509; hg19: chr4-81123159;