2-183158335-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_138285.5(NUP35):c.662C>T(p.Ala221Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUP35 NM_138285.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59

Genes affected

NUP35 (HGNC:29797): (nucleoporin 35) This gene encodes a member of the nucleoporin family. The encoded protein contains two membrane binding regions, is localized to the nuclear rim, and is part of the nuclear pore complex. All molecules entering or leaving the nucleus either diffuse through or are actively transported by the nuclear pore complex. Alternative splicing results in multiple transcript variants. Pseudogenes of this gene have been defined on chromosomes 7 and 10. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUP35	NM_138285.5	c.662C>T	p.Ala221Val	missense_variant	7/9	ENST00000295119.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUP35	ENST00000295119.9	c.662C>T	p.Ala221Val	missense_variant	7/9	1	NM_138285.5	P1
NUP35	ENST00000409798.5	c.611C>T	p.Ala204Val	missense_variant	8/10	2
NUP35	ENST00000479162.5	n.559C>T		non_coding_transcript_exon_variant	6/7	2
NUP35	ENST00000374930.7	c.*61C>T		3_prime_UTR_variant, NMD_transcript_variant	6/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2021

The c.662C>T (p.A221V) alteration is located in exon 7 (coding exon 7) of the NUP35 gene. This alteration results from a C to T substitution at nucleotide position 662, causing the alanine (A) at amino acid position 221 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.48
Sift	Benign	0.077	T;T
Sift4G	Benign	0.14	T;T
Polyphen		1.0	.;D
Vest4		0.82
MutPred		0.75		.;Loss of disorder (P = 0.0524);
MVP		0.84
MPC		0.74
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.69
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.39		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-184023063;