NM_000269.3:c.*312G>C

Variant names:

• chr17-51162157-G-C
• rs2318785
• NM_000269.3:c.*312G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000269.3(NME1):​c.*312G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 274,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: NME1 NM_000269.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.25
• Publications: 11 publications found

Genes affected

NME1 (HGNC:7849): (NME/NM23 nucleoside diphosphate kinase 1) This gene (NME1) was identified because of its reduced mRNA transcript levels in highly metastatic cells. Nucleoside diphosphate kinase (NDK) exists as a hexamer composed of 'A' (encoded by this gene) and 'B' (encoded by NME2) isoforms. Mutations in this gene have been identified in aggressive neuroblastomas. Two transcript variants encoding different isoforms have been found for this gene. Co-transcription of this gene and the neighboring downstream gene (NME2) generates naturally-occurring transcripts (NME1-NME2), which encodes a fusion protein comprised of sequence sharing identity with each individual gene product. [provided by RefSeq, Jul 2008]

NME1-NME2 (HGNC:33531): (NME1-NME2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring NME1 and NME2 genes. The significance of this read-through transcription and the function of the resulting protein product have not yet been determined. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Nov 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000269.3. 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
	NME1	NM_000269.3	MANE Select	c.*312G>C		3_prime_UTR	Exon 5 of 5	NP_000260.1	P15531-1
	NME1-NME2	NM_001018136.3		c.341+885G>C		intron	N/A	NP_001018146.1
	NME1-NME2	NR_037149.2		n.669+885G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NME1	ENST00000393196.8	TSL:1 MANE Select	c.*312G>C		3_prime_UTR	Exon 5 of 5	ENSP00000376892.3	P15531-1
	NME1-NME2	ENST00000393193.6	TSL:2	c.341+885G>C		intron	N/A	ENSP00000376889.2
	NME1	ENST00000511355.5	TSL:5	c.*1039G>C		3_prime_UTR	Exon 4 of 4	ENSP00000428553.1	E5RHP0

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151752 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000816 AC: 1 AN: 122482 Hom.: 0 Cov.: 0 AF XY: 0.0000153 AC XY: 1 AN XY: 65432

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 3940

American (AMR) AF: 0.00 AC: 0 AN: 5814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3140

East Asian (EAS) AF: 0.00 AC: 0 AN: 6270

South Asian (SAS) AF: 0.00 AC: 0 AN: 18640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 428

European-Non Finnish (NFE) AF: 0.0000138 AC: 1 AN: 72584

Other (OTH) AF: 0.00 AC: 0 AN: 6392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151752 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74084

African (AFR) AF: 0.00 AC: 0 AN: 41280

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10522

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 20489

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.26
DANN	Benign	0.46
PhyloP100		-3.3

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: rs2318785; hg19: chr17-49239518;