Genetic Variant NDC1:p.Thr586Met (chr1-53787201-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018087.5(NDC1):c.1757C>T(p.Thr586Met) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,610,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

NDC1
NM_018087.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.18

Publications

1 publications found

Variant links:

Genes affected

NDC1 (HGNC:25525): (NDC1 transmembrane nucleoporin) A structural constituent of nuclear pore. Involved in nuclear pore complex assembly and nuclear pore localization. Located in actin cytoskeleton; nuclear membrane; and plasma membrane. Part of nuclear pore. [provided by Alliance of Genome Resources, Apr 2022]

NDC1 Gene-Disease associations (from GenCC):

polyneuropathy
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

NDC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018087.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDC1	NM_018087.5	MANE Select	c.1757C>T	p.Thr586Met	missense	Exon 16 of 18	NP_060557.3
NDC1	NM_001168551.2		c.1637C>T	p.Thr546Met	missense	Exon 16 of 18	NP_001162023.1	Q9BTX1-5
NDC1	NR_033142.2		n.1671C>T		non_coding_transcript_exon	Exon 15 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDC1	ENST00000371429.4	TSL:1 MANE Select	c.1757C>T	p.Thr586Met	missense	Exon 16 of 18	ENSP00000360483.3	Q9BTX1-1
NDC1	ENST00000923529.1		c.1778C>T	p.Thr593Met	missense	Exon 16 of 18	ENSP00000593588.1
NDC1	ENST00000874541.1		c.1754C>T	p.Thr585Met	missense	Exon 16 of 18	ENSP00000544600.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151414

Hom.:

Cov.:

show subpopulations

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:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

248680

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1458724

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725802

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33424

American (AMR)

AF:

0.0000225

AC:

AN:

44530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1110540

Other (OTH)

AF:

0.0000663

AC:

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151414

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73856

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41142

American (AMR)

AF:

0.00

AC:

AN:

15162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000209

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67958

Other (OTH)

AF:

0.000480

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.5

PhyloP100

6.2

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.35

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.56

MVP

0.40

MPC

0.57

ClinPred

0.88

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.42

Mutation Taster

=70/30

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over