2-183130414-G-C

Variant names:

• chr2-183130414-G-C
• rs9333283
• NM_138285.5:c.212-4G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138285.5(NUP35):​c.212-4G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000164 in 1,219,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: NUP35 NM_138285.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001680
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.250
• Publications: 0 publications found

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]

ENSG00000224643 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUP35	NM_138285.5	c.212-4G>C		splice_region_variant, intron_variant	Intron 2 of 8	ENST00000295119.9	NP_612142.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUP35	ENST00000295119.9	c.212-4G>C		splice_region_variant, intron_variant	Intron 2 of 8	1	NM_138285.5	ENSP00000295119.4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000164 AC: 2 AN: 1219280 Hom.: 0 Cov.: 32 AF XY: 0.00000163 AC XY: 1 AN XY: 612472

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26112

American (AMR) AF: 0.00 AC: 0 AN: 37228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22640

East Asian (EAS) AF: 0.00 AC: 0 AN: 35506

South Asian (SAS) AF: 0.0000265 AC: 2 AN: 75456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3812

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 917908

Other (OTH) AF: 0.00 AC: 0 AN: 50970

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.3
DANN	Benign	0.49
PhyloP100		-0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0040
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: rs9333283; hg19: chr2-183995142;