dbSNP rs121908563: POLH:p.Gln126Lys (chr6-43587375-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006502.3(POLH):c.376C>A(p.Gln126Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

POLH
NM_006502.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.48

Publications

0 publications found

Variant links:

Genes affected

POLH (HGNC:9181): (DNA polymerase eta) This gene encodes a member of the Y family of specialized DNA polymerases. It copies undamaged DNA with a lower fidelity than other DNA-directed polymerases. However, it accurately replicates UV-damaged DNA; when thymine dimers are present, this polymerase inserts the complementary nucleotides in the newly synthesized DNA, thereby bypassing the lesion and suppressing the mutagenic effect of UV-induced DNA damage. This polymerase is thought to be involved in hypermutation during immunoglobulin class switch recombination. Mutations in this gene result in XPV, a variant type of xeroderma pigmentosum. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

POLH Gene-Disease associations (from GenCC):

xeroderma pigmentosum variant type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp

POLH links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22020024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLH	NM_006502.3 link	c.376C>A	p.Gln126Lys	missense_variant	Exon 4 of 11	ENST00000372236.9	NP_006493.1	Q9Y253-1A0A024RD62
POLH	NM_001291970.2 link	c.376C>A	p.Gln126Lys	missense_variant	Exon 4 of 11		NP_001278899.1	Q9Y253-2
POLH	XM_047418900.1 link	c.-244C>A		5_prime_UTR_variant	Exon 1 of 8		XP_047274856.1
POLH	NM_001291969.2 link	c.118+4234C>A		intron_variant	Intron 2 of 8		NP_001278898.1	B3KN75

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POLH	ENST00000372236.9 link	c.376C>A	p.Gln126Lys	missense_variant	Exon 4 of 11	1	NM_006502.3	ENSP00000361310.4	Q9Y253-1
POLH	ENST00000372226.1 link	c.376C>A	p.Gln126Lys	missense_variant	Exon 4 of 11	1		ENSP00000361300.1	Q9Y253-2
POLH	ENST00000443535.1 link	c.190C>A	p.Gln64Lys	missense_variant	Exon 3 of 3	2		ENSP00000405320.1	Q5JTF2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461690

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111824

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.17

T;.;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.038

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.35

N;N;.

PhyloP100

4.5

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.24

T;T;T

Sift4G

Benign

0.43

T;T;T

Polyphen

0.020

B;.;.

Vest4

0.26

MutPred

0.50

Gain of ubiquitination at Q126 (P = 0.0238);Gain of ubiquitination at Q126 (P = 0.0238);.;

MVP

0.73

MPC

0.27

ClinPred

0.43

GERP RS

3.9

Varity_R

0.41

gMVP

0.56

Mutation Taster

=71/29

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over