Genetic Variant NDC1:p.Ser439Thr (chr1-53797052-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018087.5(NDC1):c.1315T>A(p.Ser439Thr) 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 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. S439P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NDC1
NM_018087.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0130

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.079612285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDC1	NM_018087.5 link	c.1315T>A	p.Ser439Thr	missense_variant	Exon 12 of 18	ENST00000371429.4	NP_060557.3	Q9BTX1-1
NDC1	NM_001168551.2 link	c.1195T>A	p.Ser399Thr	missense_variant	Exon 12 of 18		NP_001162023.1	Q9BTX1-5
NDC1	XM_011541766.3 link	c.1312T>A	p.Ser438Thr	missense_variant	Exon 12 of 18		XP_011540068.1
NDC1	NR_033142.2 link	n.1229T>A		non_coding_transcript_exon_variant	Exon 11 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDC1	ENST00000371429.4 link	c.1315T>A	p.Ser439Thr	missense_variant	Exon 12 of 18	1	NM_018087.5	ENSP00000360483.3		Q9BTX1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.012

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.64

M_CAP

Benign

0.010

MetaRNN

Benign

0.080

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.88

PhyloP100

0.013

PrimateAI

Benign

0.34

PROVEAN

Benign

0.24

REVEL

Benign

0.022

Sift

Benign

0.038

Sift4G

Benign

0.57

Polyphen

0.026

Vest4

0.18

MutPred

0.33

Gain of glycosylation at T440 (P = 0.0936);

MVP

0.38

MPC

0.14

ClinPred

0.043

GERP RS

-1.3

Varity_R

0.039

gMVP

0.30

Mutation Taster

=92/8

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over