rs1060501848

chr19-50417222-G-Cchr19-50417222-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002691.4(POLD1):c.3171G>C(p.Gln1057His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1057R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57

Genes affected

POLD1 (HGNC:9175): (DNA polymerase delta 1, catalytic subunit) This gene encodes the 125-kDa catalytic subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.3171G>C	p.Gln1057His	missense_variant	26/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.3171G>C	p.Gln1057His	missense_variant	26/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.0024	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;.;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.76	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.0	M;.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.7	D;.;.;.
REVEL	Benign	0.24
Sift	Uncertain	0.014	D;.;.;.
Sift4G	Uncertain	0.053	T;T;T;T
Polyphen		0.39	B;.;.;B
Vest4		0.76
MutPred		0.46		Gain of catalytic residue at C1058 (P = 0.1149);.;.;Gain of catalytic residue at C1058 (P = 0.1149);
MVP		0.67
MPC		1.6
ClinPred		0.98	D
GERP RS		2.0
Varity_R		0.69
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50920479;