1-53772486-C-T

Variant names:

• chr1-53772486-C-T
• rs770330848
• NM_018087.5:c.1804G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018087.5(NDC1):​c.1804G>A​(p.Val602Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: NDC1 NM_018087.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27306557).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDC1	NM_018087.5	MANE Select	c.1804G>A	p.Val602Ile	missense	Exon 17 of 18	NP_060557.3
	NDC1	NM_001168551.2		c.1684G>A	p.Val562Ile	missense	Exon 17 of 18	NP_001162023.1	Q9BTX1-5
	NDC1	NR_033142.2		n.1718G>A		non_coding_transcript_exon	Exon 16 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDC1	ENST00000371429.4	TSL:1 MANE Select	c.1804G>A	p.Val602Ile	missense	Exon 17 of 18	ENSP00000360483.3	Q9BTX1-1
	NDC1	ENST00000923529.1		c.1825G>A	p.Val609Ile	missense	Exon 17 of 18	ENSP00000593588.1
	NDC1	ENST00000874541.1		c.1801G>A	p.Val601Ile	missense	Exon 17 of 18	ENSP00000544600.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250894 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460236 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 726480

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111016

Other (OTH) AF: 0.00 AC: 0 AN: 60284

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.15
Sift	Benign	0.084	T
Sift4G	Benign	0.064	T
Polyphen		0.062	B
Vest4		0.42
MutPred		0.50		Gain of methylation at K604 (P = 0.118)
MVP		0.34
MPC		0.27
ClinPred		0.70	D
GERP RS		5.3
Varity_R		0.075
gMVP		0.28
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs770330848; hg19: chr1-54238159;