rs9333554

Positions:

chr6-43614166-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006502.3(POLH):c.1751T>C(p.Leu584Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,614,212 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L584L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 43 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 43 hom. )

Consequence

POLH
NM_006502.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0460

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 links:

POLR1C (HGNC:):

POLR1C links:

GTPBP2 (HGNC:4670): (GTP binding protein 2) GTP-binding proteins, or G proteins, constitute a superfamily capable of binding GTP or GDP. G proteins are activated by binding GTP and are inactivated by hydrolyzing GTP to GDP. This general mechanism enables G proteins to perform a wide range of biologic activities.[supplied by OMIM, Jan 2003]

GTPBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018085241).

BP6

Variant 6-43614166-T-C is Benign according to our data. Variant chr6-43614166-T-C is described in ClinVar as [Benign]. Clinvar id is 787831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0126 (1916/152324) while in subpopulation AFR AF= 0.044 (1828/41570). AF 95% confidence interval is 0.0423. There are 43 homozygotes in gnomad4. There are 913 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLH	NM_006502.3 linkuse as main transcript	c.1751T>C	p.Leu584Pro	missense_variant	11/11	ENST00000372236.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLH	ENST00000372236.9 linkuse as main transcript	c.1751T>C	p.Leu584Pro	missense_variant	11/11	1	NM_006502.3	P1	Q9Y253-1
POLH	ENST00000372226.1 linkuse as main transcript	c.*435T>C		3_prime_UTR_variant	11/11	1			Q9Y253-2
GTPBP2	ENST00000496137.5 linkuse as main transcript	c.*131+5953A>G		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1917

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0441

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

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:

0.000103

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.00342

AC:

860

AN:

251426

Hom.:

AF XY:

0.00239

AC XY:

325

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0485

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00134

AC:

1961

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

793

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0492

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.00258

GnomAD4 genome

AF:

0.0126

AC:

1916

AN:

152324

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

913

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0440

Gnomad4 AMR

AF:

0.00360

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00331

Hom.:

Bravo

AF:

0.0150

ESP6500AA

AF:

0.0465

AC:

205

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00409

AC:

497

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum variant type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.051

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.95

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.76

REVEL

Benign

0.057

Sift

Benign

0.28

Sift4G

Benign

0.17

Polyphen

0.0

Vest4

0.036

MVP

0.51

MPC

0.34

ClinPred

0.00062

GERP RS

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.055

gMVP

0.27

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over