chr4-2193297-T-G

Variant names:

• chr4-2193297-T-G
• rs10018786
• NM_181808.4:c.928A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181808.4(POLN):​c.928A>C​(p.Met310Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,597,796 control chromosomes in the GnomAD database, including 25,532 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (7848 hom., cov: 32)
  • Exomes 𝑓: 0.13 (17684 hom.)
• Consequence: POLN NM_181808.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.06
• Publications: 28 publications found

Genes affected

POLN (HGNC:18870): (DNA polymerase nu) This gene encodes a DNA polymerase type-A family member. The encoded protein plays a role in DNA repair and homologous recombination. This gene shares its 5' exons with some transcripts from overlapping GeneID: 79441, which encodes an augmentin-like protein complex subunit. [provided by RefSeq, Dec 2014]

ENSG00000290263 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.04666644E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181808.4. 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
	POLN	NM_181808.4	MANE Select	c.928A>C	p.Met310Leu	missense	Exon 7 of 26	NP_861524.2	Q7Z5Q5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLN	ENST00000511885.6	TSL:5 MANE Select	c.928A>C	p.Met310Leu	missense	Exon 7 of 26	ENSP00000435506.1	Q7Z5Q5-1
	POLN	ENST00000382865.5	TSL:1	c.928A>C	p.Met310Leu	missense	Exon 5 of 24	ENSP00000372316.1	Q7Z5Q5-1
	ENSG00000290263	ENST00000672725.1		n.2518A>C		non_coding_transcript_exon	Exon 9 of 19	ENSP00000500518.1	A0A5F9ZHQ7

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38741 AN: 152022 Hom.: 7830 Cov.: 32

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.0843

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.255

GnomAD2 exomes AF: 0.185 AC: 45196 AN: 244934 AF XY: 0.172

Gnomad AFR exome AF: 0.548

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.385

Gnomad FIN exome AF: 0.0938

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.128 AC: 185187 AN: 1445656 Hom.: 17684 Cov.: 29 AF XY: 0.128 AC XY: 91741 AN XY: 719512

African (AFR) AF: 0.564 AC: 18271 AN: 32420

American (AMR) AF: 0.250 AC: 10801 AN: 43166

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3701 AN: 25878

East Asian (EAS) AF: 0.353 AC: 13850 AN: 39192

South Asian (SAS) AF: 0.152 AC: 12880 AN: 84468

European-Finnish (FIN) AF: 0.0923 AC: 4919 AN: 53318

Middle Eastern (MID) AF: 0.226 AC: 1294 AN: 5724

European-Non Finnish (NFE) AF: 0.0993 AC: 109458 AN: 1101804

Other (OTH) AF: 0.168 AC: 10013 AN: 59686

GnomAD4 genome AF: 0.255 AC: 38812 AN: 152140 Hom.: 7848 Cov.: 32 AF XY: 0.253 AC XY: 18795 AN XY: 74416

African (AFR) AF: 0.545 AC: 22575 AN: 41438

American (AMR) AF: 0.245 AC: 3754 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 553 AN: 3466

East Asian (EAS) AF: 0.379 AC: 1960 AN: 5178

South Asian (SAS) AF: 0.173 AC: 836 AN: 4828

European-Finnish (FIN) AF: 0.0843 AC: 895 AN: 10620

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7419 AN: 67998

Other (OTH) AF: 0.257 AC: 543 AN: 2114

Alfa AF: 0.168 Hom.: 12667

Bravo AF: 0.284

TwinsUK AF: 0.0995 AC: 369

ALSPAC AF: 0.106 AC: 407

ESP6500AA AF: 0.535 AC: 2357

ESP6500EA AF: 0.115 AC: 991

ExAC AF: 0.192 AC: 23300

Asia WGS AF: 0.331 AC: 1152 AN: 3478

EpiCase AF: 0.120

EpiControl AF: 0.126

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	17
DANN	Benign	0.37
DEOGEN2	Benign	0.00016	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.00010	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.4	N
PhyloP100		3.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.065
MutPred		0.41		Loss of catalytic residue at M310 (P = 9e-04)
MPC		0.068
ClinPred		0.0020	T
GERP RS		4.6
Varity_R		0.31
gMVP		0.36
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs10018786; hg19: chr4-2195024; COSMIC: COSV67026057;