7-44074408-C-T

Variant names:

• chr7-44074408-C-T
• rs930869351
• NM_013284.4:c.958G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_013284.4(POLM):​c.958G>A​(p.Gly320Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,556,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: POLM NM_013284.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.17
• Publications: 0 publications found

Genes affected

POLM (HGNC:9185): (DNA polymerase mu) Predicted to enable DNA-directed DNA polymerase activity. Predicted to be involved in double-strand break repair via nonhomologous end joining. Predicted to act upstream of or within B cell differentiation and somatic hypermutation of immunoglobulin genes. Predicted to be located in nucleoplasm. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013284.4. 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
	POLM	NM_013284.4	MANE Select	c.958G>A	p.Gly320Ser	missense	Exon 7 of 11	NP_037416.1	Q9NP87-1
	POLM	NM_001362683.2		c.958G>A	p.Gly320Ser	missense	Exon 7 of 11	NP_001349612.1
	POLM	NM_001284330.2		c.821G>A	p.Arg274Gln	missense	Exon 6 of 9	NP_001271259.1	Q9NP87-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLM	ENST00000242248.10	TSL:1 MANE Select	c.958G>A	p.Gly320Ser	missense	Exon 7 of 11	ENSP00000242248.5	Q9NP87-1
	POLM	ENST00000395831.7	TSL:1	c.821G>A	p.Arg274Gln	missense	Exon 6 of 9	ENSP00000379174.3	Q9NP87-3
	POLM	ENST00000335195.10	TSL:1	c.950G>A	p.Arg317Gln	missense	Exon 7 of 10	ENSP00000335141.6	Q9NP87-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000186 AC: 3 AN: 161058 AF XY: 0.0000234

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000642

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.00000997 AC: 14 AN: 1404558 Hom.: 0 Cov.: 32 AF XY: 0.0000130 AC XY: 9 AN XY: 693312

African (AFR) AF: 0.00 AC: 0 AN: 31966

American (AMR) AF: 0.00 AC: 0 AN: 36232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 36366

South Asian (SAS) AF: 0.0000754 AC: 6 AN: 79606

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49300

Middle Eastern (MID) AF: 0.000356 AC: 2 AN: 5622

European-Non Finnish (NFE) AF: 0.00000462 AC: 5 AN: 1082082

Other (OTH) AF: 0.00 AC: 0 AN: 58204

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000731 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Benign	0.89
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-1.1	T
PhyloP100		3.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.27
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.75		Gain of phosphorylation at G320 (P = 0.072)
MVP		0.44
MPC		0.53
ClinPred		0.63	D
GERP RS		5.6
Varity_R		0.69
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs930869351; hg19: chr7-44114007;