3-48296757-C-T

Variant names:

• chr3-48296757-C-T
• rs370989621
• NM_001308426.2:c.163G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001308426.2(NME6):​c.163G>A​(p.Asp55Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,456 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D55Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NME6 NM_001308426.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37

Genes affected

NME6 (HGNC:20567): (NME/NM23 nucleoside diphosphate kinase 6) Nucleoside diphosphate (NDP) kinases (EC 2.7.4.6), such as NME6, are ubiquitous enzymes that catalyze transfer of gamma-phosphates, via a phosphohistidine intermediate, between nucleoside and dioxynucleoside tri- and diphosphates (Mehus et al., 1999 [PubMed 10453732]).[supplied by OMIM, Jul 2010]

ZNF589 (HGNC:16747): (zinc finger protein 589) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in negative regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27111864).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NME6	NM_001308426.2	c.163G>A	p.Asp55Asn	missense_variant	Exon 3 of 6	ENST00000442597.6	NP_001295355.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NME6	ENST00000442597.6	c.163G>A	p.Asp55Asn	missense_variant	Exon 3 of 6	1	NM_001308426.2	ENSP00000406642.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251162 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135764

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461456 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	.;.;T;T;T;.;T;T;T;.;.;.
Eigen	Benign	0.076
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	.;D;.;D;.;D;.;.;T;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.6	M;.;M;M;M;M;M;M;.;M;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.9	D;N;.;N;N;D;N;N;N;D;N;D
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D;T;.;D;D;D;D;D;T;D;D;D
Sift4G	Uncertain	0.017	D;T;.;T;T;D;T;T;T;D;T;.
Polyphen		0.99	D;.;B;B;B;P;B;B;.;D;B;.
Vest4		0.36
MutPred		0.48		Gain of MoRF binding (P = 0.0338);.;Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);.;Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);
MVP		0.60
MPC		0.73
ClinPred		0.84	D
GERP RS		3.6
Varity_R		0.44
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs370989621; hg19: chr3-48338247;