3-138318215-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001349018.2(NME9):c.200A>G(p.Glu67Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,458,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NME9 NM_001349018.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.62

Genes affected

NME9 (HGNC:21343): (NME/NM23 family member 9) Predicted to enable nucleoside diphosphate kinase activity. Predicted to be involved in nucleotide metabolic process. Predicted to be located in dynein axonemal particle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NME9	NM_001349018.2	c.200A>G	p.Glu67Gly	missense_variant	4/11	ENST00000333911.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NME9	ENST00000333911.9	c.200A>G	p.Glu67Gly	missense_variant	4/11	1	NM_001349018.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251388 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135868

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458708 Hom.: 0 Cov.: 28 AF XY: 0.00000551 AC XY: 4 AN XY: 725884

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The c.134A>G (p.E45G) alteration is located in exon 6 (coding exon 3) of the NME9 gene. This alteration results from a A to G substitution at nucleotide position 134, causing the glutamic acid (E) at amino acid position 45 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;.;D;D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	0.95	D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Uncertain	0.37
Sift	Benign	0.038	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;T
Polyphen		1.0	D;D;D;.
Vest4		0.67
MVP		0.42
MPC		0.84
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.52
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs368027073; hg19: chr3-138037057;