22-42599699-A-T

Variant names:

• chr22-42599699-A-T
• rs762581666
• NM_032311.5:c.632T>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032311.5(POLDIP3):​c.632T>A​(p.Met211Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: POLDIP3 NM_032311.5 missense, splice_region
• Scores: Splicing: ADA: 0.00004773
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0430

Genes affected

POLDIP3 (HGNC:23782): (DNA polymerase delta interacting protein 3) This gene encodes an RRM (RNA recognition motif)-containing protein that participates in the regulation of translation by recruiting ribosomal protein S6 kinase beta-1 to mRNAs. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ENSG00000289517 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053907156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLDIP3	NM_032311.5	c.632T>A	p.Met211Lys	missense_variant, splice_region_variant	Exon 4 of 9	ENST00000252115.10	NP_115687.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLDIP3	ENST00000252115.10	c.632T>A	p.Met211Lys	missense_variant, splice_region_variant	Exon 4 of 9	1	NM_032311.5	ENSP00000252115.5
ENSG00000289517	ENST00000617178.5	n.*1493T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 14	1		ENSP00000482500.2
ENSG00000289517	ENST00000617178.5	n.*1493T>A		3_prime_UTR_variant	Exon 9 of 14	1		ENSP00000482500.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250798 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

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: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.632T>A (p.M211K) alteration is located in exon 4 (coding exon 4) of the POLDIP3 gene. This alteration results from a T to A substitution at nucleotide position 632, causing the methionine (M) at amino acid position 211 to be replaced by a lysine (K). 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	Benign	0.092
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.16
DANN	Benign	0.61
DEOGEN2	Benign	0.0028	.;T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.65	T;T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.054	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	.;L;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.24	N;N;.;.
REVEL	Benign	0.050
Sift	Benign	0.14	T;T;.;.
Sift4G	Benign	0.55	T;T;T;T
Polyphen		0.0030	B;B;.;.
Vest4		0.31
MutPred		0.43		.;Gain of ubiquitination at M211 (P = 0.0203);.;.;
MVP		0.21
MPC		0.13
ClinPred		0.024	T
GERP RS		-3.0
Varity_R		0.15
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.080
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: rs762581666; hg19: chr22-42995705;