6-43610590-C-T

Variant names:

• chr6-43610590-C-T
• rs147564503
• NM_006502.3:c.1111C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_006502.3(POLH):​c.1111C>T​(p.Arg371Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R371R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: POLH NM_006502.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.22
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000401 (61/152128) while in subpopulation AMR AF = 0.00151 (23/15260). AF 95% confidence interval is 0.00103. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1111C>T	p.Arg371Cys	missense	Exon 10 of 11	NP_006493.1	Q9Y253-1
	POLH	NM_001291969.2		c.739C>T	p.Arg247Cys	missense	Exon 8 of 9	NP_001278898.1
	POLH	NM_001291970.2		c.1111C>T	p.Arg371Cys	missense	Exon 10 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.1111C>T	p.Arg371Cys	missense	Exon 10 of 11	ENSP00000361310.4	Q9Y253-1
	POLH	ENST00000372226.1	TSL:1	c.1111C>T	p.Arg371Cys	missense	Exon 10 of 11	ENSP00000361300.1	Q9Y253-2
	POLH	ENST00000921322.1		c.1111C>T	p.Arg371Cys	missense	Exon 11 of 12	ENSP00000591381.1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152128 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000294 AC: 74 AN: 251356 AF XY: 0.000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000582 AC: 851 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.000551 AC XY: 401 AN XY: 727196

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.000559 AC: 25 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000710 AC: 790 AN: 1111936

Other (OTH) AF: 0.000580 AC: 35 AN: 60392

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152128 Hom.: 0 Cov.: 31 AF XY: 0.000457 AC XY: 34 AN XY: 74322

African (AFR) AF: 0.000145 AC: 6 AN: 41422

American (AMR) AF: 0.00151 AC: 23 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000380 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000327

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0013	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.79
MPC		0.91
ClinPred		0.32	T
GERP RS		5.9
Varity_R		0.51
gMVP		0.73
Mutation Taster		=32/68	disease causing

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: rs147564503; hg19: chr6-43578327; COSMIC: COSV64780683;