chr6-43613848-C-T

Variant summary

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

The NM_006502.3(POLH):​c.1433C>T​(p.Thr478Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000484 in 1,614,172 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00074 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00046 ( 3 hom. )

Consequence

POLH
NM_006502.3 missense

Scores

3
15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.538
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0035762787).
BP6
Variant 6-43613848-C-T is Benign according to our data. Variant chr6-43613848-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 717328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000735 (112/152298) while in subpopulation EAS AF= 0.0197 (102/5184). AF 95% confidence interval is 0.0166. There are 1 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLHNM_006502.3 linkuse as main transcriptc.1433C>T p.Thr478Met missense_variant 11/11 ENST00000372236.9 NP_006493.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLHENST00000372236.9 linkuse as main transcriptc.1433C>T p.Thr478Met missense_variant 11/111 NM_006502.3 ENSP00000361310 P1Q9Y253-1
POLHENST00000372226.1 linkuse as main transcriptc.*117C>T 3_prime_UTR_variant 11/111 ENSP00000361300 Q9Y253-2
GTPBP2ENST00000496137.5 linkuse as main transcriptc.*131+6271G>A intron_variant, NMD_transcript_variant 3 ENSP00000436973

Frequencies

GnomAD3 genomes
AF:
0.000736
AC:
112
AN:
152180
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0196
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000959
GnomAD3 exomes
AF:
0.00152
AC:
383
AN:
251428
Hom.:
3
AF XY:
0.00152
AC XY:
207
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0188
Gnomad SAS exome
AF:
0.000686
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00130
GnomAD4 exome
AF:
0.000458
AC:
670
AN:
1461874
Hom.:
3
Cov.:
32
AF XY:
0.000485
AC XY:
353
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0137
Gnomad4 SAS exome
AF:
0.000626
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000180
Gnomad4 OTH exome
AF:
0.000778
GnomAD4 genome
AF:
0.000735
AC:
112
AN:
152298
Hom.:
1
Cov.:
32
AF XY:
0.000779
AC XY:
58
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0197
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000949
Alfa
AF:
0.00105
Hom.:
2
Bravo
AF:
0.00110
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00149
AC:
181
Asia WGS
AF:
0.00779
AC:
27
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Xeroderma pigmentosum variant type Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 27, 2021- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 18, 2022- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.15
T
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.66
FATHMM_MKL
Benign
0.21
N
LIST_S2
Benign
0.82
T
MetaRNN
Benign
0.0036
T
MetaSVM
Benign
-0.85
T
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-1.7
N
REVEL
Benign
0.19
Sift
Uncertain
0.015
D
Sift4G
Benign
0.077
T
Polyphen
0.97
D
Vest4
0.17
MVP
0.66
MPC
0.47
ClinPred
0.046
T
GERP RS
-3.9
Varity_R
0.028
gMVP
0.28

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

LitVar

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

Other links and lift over

dbSNP: rs9296419; hg19: chr6-43581585; COSMIC: COSV64779035; API