6-43605497-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006502.3(POLH):c.1074+178T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00688 in 538,036 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (104 hom., cov: 27)
  • Exomes 𝑓: 0.0022 (33 hom.)
• Consequence: POLH NM_006502.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.669

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]

POLR1C (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-43605497-T-G is Benign according to our data. Variant chr6-43605497-T-G is described in ClinVar as [Benign]. Clinvar id is 1258371.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLH	NM_006502.3	c.1074+178T>G		intron_variant		ENST00000372236.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLH	ENST00000372236.9	c.1074+178T>G		intron_variant		1	NM_006502.3	P1
POLH	ENST00000372226.1	c.1074+178T>G		intron_variant		1
GTPBP2	ENST00000496137.5	c.*132-115A>C		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 2820 AN: 142526 Hom.: 103 Cov.: 27

Gnomad AFR AF: 0.0708

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00683

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000474

Gnomad FIN AF: 0.000108

Gnomad MID AF: 0.00331

Gnomad NFE AF: 0.000181

Gnomad OTH AF: 0.0103

GnomAD4 exome AF: 0.00220 AC: 871 AN: 395406 Hom.: 33 AF XY: 0.00181 AC XY: 388 AN XY: 213996

Gnomad4 AFR exome AF: 0.0653

Gnomad4 AMR exome AF: 0.00401

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000320

Gnomad4 FIN exome AF: 0.0000452

Gnomad4 NFE exome AF: 0.0000791

Gnomad4 OTH exome AF: 0.00357

GnomAD4 genome AF: 0.0198 AC: 2828 AN: 142630 Hom.: 104 Cov.: 27 AF XY: 0.0196 AC XY: 1351 AN XY: 69070

Gnomad4 AFR AF: 0.0707

Gnomad4 AMR AF: 0.00689

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000475

Gnomad4 FIN AF: 0.000108

Gnomad4 NFE AF: 0.000181

Gnomad4 OTH AF: 0.0102

Alfa AF: 0.0182 Hom.: 8

Bravo AF: 0.0246

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	3.7
Dann	Benign	0.34

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

Other links and lift over

dbSNP: rs114052434; hg19: chr6-43573234;