chr3-48296738-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_001308426.2(NME6):​c.182G>A​(p.Arg61Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,611,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

NME6
NM_001308426.2 missense

Scores

1
18

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.479
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07986179).
BP6
Variant 3-48296738-C-T is Benign according to our data. Variant chr3-48296738-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3406333.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NME6NM_001308426.2 linkc.182G>A p.Arg61Gln missense_variant Exon 3 of 6 ENST00000442597.6 NP_001295355.1 O75414-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NME6ENST00000442597.6 linkc.182G>A p.Arg61Gln missense_variant Exon 3 of 6 1 NM_001308426.2 ENSP00000406642.1 O75414-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152074
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
250828
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135620
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000116
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:
0.00000685
AC:
10
AN:
1459884
Hom.:
0
Cov.:
30
AF XY:
0.00000551
AC XY:
4
AN XY:
726394
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000134
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152074
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74256
show subpopulations
Gnomad4 AFR
AF:
0.0000725
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000314
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Jun 25, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
13
DANN
Uncertain
0.98
DEOGEN2
Benign
0.015
.;.;T;T;T;.;T;T;T;.;.;.
Eigen
Benign
-0.85
Eigen_PC
Benign
-0.78
FATHMM_MKL
Benign
0.44
N
LIST_S2
Benign
0.76
.;T;.;T;.;T;.;.;T;T;T;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.080
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.34
N;.;N;N;N;N;N;N;.;N;.;.
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.45
N;N;.;N;N;N;N;N;N;N;N;N
REVEL
Benign
0.024
Sift
Benign
0.13
T;T;.;T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.35
T;T;.;T;T;T;T;T;T;T;T;.
Polyphen
0.20
B;.;B;B;B;B;B;B;.;B;B;.
Vest4
0.25
MutPred
0.36
Loss of MoRF binding (P = 0.0747);.;Loss of MoRF binding (P = 0.0747);Loss of MoRF binding (P = 0.0747);Loss of MoRF binding (P = 0.0747);Loss of MoRF binding (P = 0.0747);Loss of MoRF binding (P = 0.0747);Loss of MoRF binding (P = 0.0747);.;Loss of MoRF binding (P = 0.0747);Loss of MoRF binding (P = 0.0747);Loss of MoRF binding (P = 0.0747);
MVP
0.30
MPC
0.29
ClinPred
0.014
T
GERP RS
-0.53
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.027
gMVP
0.36

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs760749558; hg19: chr3-48338228; API