rs6941583

Variant names:

• chr6-43614354-A-T
• rs6941583
• NM_006502.3:c.1939A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006502.3(POLH):​c.1939A>T​(p.Met647Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0491 in 1,612,354 control chromosomes in the GnomAD database, including 5,137 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M647R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (2157 hom., cov: 32)
  • Exomes 𝑓: 0.042 (2980 hom.)
• Consequence: POLH NM_006502.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.90
• Publications: 29 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, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013748407).
• BP6: Variant 6-43614354-A-T is Benign according to our data. Variant chr6-43614354-A-T is described in ClinVar as Benign. ClinVar VariationId is 259989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

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.1939A>T	p.Met647Leu	missense	Exon 11 of 11	NP_006493.1
	POLH	NM_001291969.2		c.1567A>T	p.Met523Leu	missense	Exon 9 of 9	NP_001278898.1
	POLH	NM_001291970.2		c.*623A>T		3_prime_UTR	Exon 11 of 11	NP_001278899.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLH	ENST00000372236.9	TSL:1 MANE Select	c.1939A>T	p.Met647Leu	missense	Exon 11 of 11	ENSP00000361310.4
	POLH	ENST00000372226.1	TSL:1	c.*623A>T		3_prime_UTR	Exon 11 of 11	ENSP00000361300.1
	POLH	ENST00000921322.1		c.1939A>T	p.Met647Leu	missense	Exon 12 of 12	ENSP00000591381.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17193 AN: 152102 Hom.: 2139 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0570

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.0366

Gnomad SAS AF: 0.0826

Gnomad FIN AF: 0.0380

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0310

Gnomad OTH AF: 0.0899

GnomAD2 exomes AF: 0.0591 AC: 14840 AN: 251254 AF XY: 0.0560

Gnomad AFR exome AF: 0.321

Gnomad AMR exome AF: 0.0284

Gnomad ASJ exome AF: 0.0538

Gnomad EAS exome AF: 0.0391

Gnomad FIN exome AF: 0.0388

Gnomad NFE exome AF: 0.0318

Gnomad OTH exome AF: 0.0509

GnomAD4 exome AF: 0.0424 AC: 61839 AN: 1460134 Hom.: 2980 Cov.: 32 AF XY: 0.0428 AC XY: 31042 AN XY: 726010

African (AFR) AF: 0.321 AC: 10745 AN: 33428

American (AMR) AF: 0.0327 AC: 1459 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 1440 AN: 26108

East Asian (EAS) AF: 0.0340 AC: 1346 AN: 39636

South Asian (SAS) AF: 0.0800 AC: 6899 AN: 86234

European-Finnish (FIN) AF: 0.0365 AC: 1948 AN: 53408

Middle Eastern (MID) AF: 0.0681 AC: 392 AN: 5760

European-Non Finnish (NFE) AF: 0.0309 AC: 34310 AN: 1110570

Other (OTH) AF: 0.0547 AC: 3300 AN: 60306

GnomAD4 genome AF: 0.113 AC: 17262 AN: 152220 Hom.: 2157 Cov.: 32 AF XY: 0.112 AC XY: 8316 AN XY: 74440

African (AFR) AF: 0.311 AC: 12894 AN: 41478

American (AMR) AF: 0.0570 AC: 872 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 170 AN: 3472

East Asian (EAS) AF: 0.0367 AC: 190 AN: 5176

South Asian (SAS) AF: 0.0825 AC: 398 AN: 4824

European-Finnish (FIN) AF: 0.0380 AC: 404 AN: 10622

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0310 AC: 2111 AN: 68022

Other (OTH) AF: 0.0899 AC: 190 AN: 2114

Alfa AF: 0.0463 Hom.: 287

Bravo AF: 0.123

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.305 AC: 1343

ESP6500EA AF: 0.0308 AC: 265

ExAC AF: 0.0654 AC: 7941

Asia WGS AF: 0.0850 AC: 297 AN: 3478

EpiCase AF: 0.0337

EpiControl AF: 0.0344

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Xeroderma pigmentosum variant type (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.84
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.9
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.14
Sift	Benign	0.51	T
Sift4G	Benign	0.61	T
Polyphen		0.030	B
Vest4		0.11
MutPred		0.19		Loss of catalytic residue at M647 (P = 0.1213)
MPC		0.20
ClinPred		0.016	T
GERP RS		5.7
Varity_R		0.41
gMVP		0.47
Mutation Taster		=91/9	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: rs6941583; hg19: chr6-43582091; COSMIC: COSV64778879;