6-43614198-A-G

Variant names:

• chr6-43614198-A-G
• rs9333555
• NM_006502.3:c.1783A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006502.3(POLH):​c.1783A>G​(p.Met595Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 1,613,394 control chromosomes in the GnomAD database, including 643 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (35 hom., cov: 32)
  • Exomes 𝑓: 0.026 (608 hom.)
• Consequence: POLH NM_006502.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.645
• Publications: 23 publications found

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]

GTPBP2 Gene-Disease associations (from GenCC):

• Jaberi-Elahi syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00202626).
• BP6: Variant 6-43614198-A-G is Benign according to our data. Variant chr6-43614198-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0185 (2818/152306) while in subpopulation SAS AF = 0.0425 (205/4828). AF 95% confidence interval is 0.0377. There are 35 homozygotes in GnomAd4. There are 1305 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006502.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLH	NM_006502.3	MANE Select	c.1783A>G	p.Met595Val	missense	Exon 11 of 11	NP_006493.1	Q9Y253-1
	POLH	NM_001291969.2		c.1411A>G	p.Met471Val	missense	Exon 9 of 9	NP_001278898.1
	POLH	NM_001291970.2		c.*467A>G		3_prime_UTR	Exon 11 of 11	NP_001278899.1	Q9Y253-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLH	ENST00000372236.9	TSL:1 MANE Select	c.1783A>G	p.Met595Val	missense	Exon 11 of 11	ENSP00000361310.4	Q9Y253-1
	POLH	ENST00000372226.1	TSL:1	c.*467A>G		3_prime_UTR	Exon 11 of 11	ENSP00000361300.1	Q9Y253-2
	POLH	ENST00000921322.1		c.1783A>G	p.Met595Val	missense	Exon 12 of 12	ENSP00000591381.1

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2818 AN: 152188 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0424

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0291

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0212 AC: 5322 AN: 251326 AF XY: 0.0228

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.00805

Gnomad EAS exome AF: 0.00272

Gnomad FIN exome AF: 0.00416

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.0264 AC: 38500 AN: 1461088 Hom.: 608 Cov.: 33 AF XY: 0.0266 AC XY: 19361 AN XY: 726680

African (AFR) AF: 0.00466 AC: 156 AN: 33460

American (AMR) AF: 0.0166 AC: 744 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00842 AC: 220 AN: 26122

East Asian (EAS) AF: 0.00139 AC: 55 AN: 39692

South Asian (SAS) AF: 0.0374 AC: 3222 AN: 86252

European-Finnish (FIN) AF: 0.00564 AC: 301 AN: 53414

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5768

European-Non Finnish (NFE) AF: 0.0290 AC: 32263 AN: 1111322

Other (OTH) AF: 0.0249 AC: 1503 AN: 60366

GnomAD4 genome AF: 0.0185 AC: 2818 AN: 152306 Hom.: 35 Cov.: 32 AF XY: 0.0175 AC XY: 1305 AN XY: 74468

African (AFR) AF: 0.00496 AC: 206 AN: 41568

American (AMR) AF: 0.0183 AC: 280 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5182

South Asian (SAS) AF: 0.0425 AC: 205 AN: 4828

European-Finnish (FIN) AF: 0.00414 AC: 44 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0291 AC: 1982 AN: 68024

Other (OTH) AF: 0.0194 AC: 41 AN: 2110

Alfa AF: 0.0252 Hom.: 246

Bravo AF: 0.0178

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0254 AC: 98

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0323 AC: 278

ExAC AF: 0.0224 AC: 2724

Asia WGS AF: 0.0290 AC: 101 AN: 3478

EpiCase AF: 0.0280

EpiControl AF: 0.0279

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	3	Xeroderma pigmentosum variant type (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.056
DANN	Benign	0.46
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.65
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.044
Sift	Benign	0.37	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.21
ClinPred		0.0029	T
GERP RS		-6.8
Varity_R		0.045
gMVP		0.18
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9333555; hg19: chr6-43581935; COSMIC: COSV64778874;