rs193920996

chr3-161235138-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015938.5(NMD3):c.503C>T(p.Thr168Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,370,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: NMD3 NM_015938.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.36

Genes affected

NMD3 (HGNC:24250): (NMD3 ribosome export adaptor) Ribosomal 40S and 60S subunits associate in the nucleolus and are exported to the cytoplasm. The protein encoded by this gene is involved in the passage of the 60S subunit through the nuclear pore complex and into the cytoplasm. Several transcript variants exist for this gene, but the full-length natures of only two have been described to date. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NMD3	NM_015938.5	c.503C>T	p.Thr168Ile	missense_variant	7/16	ENST00000351193.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NMD3	ENST00000351193.7	c.503C>T	p.Thr168Ile	missense_variant	7/16	1	NM_015938.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1370036 Hom.: 0 Cov.: 21 AF XY: 0.00000146 AC XY: 1 AN XY: 684874

Gnomad4 AFR exome AF: 0.0000328

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;.;T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-5.7	D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		0.98, 1.0	.;D;D;.;D
Vest4		0.96, 0.96
MutPred		0.91		Gain of MoRF binding (P = 0.0686);Gain of MoRF binding (P = 0.0686);Gain of MoRF binding (P = 0.0686);Gain of MoRF binding (P = 0.0686);Gain of MoRF binding (P = 0.0686);
MVP		0.85
MPC		0.17
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.85
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs193920996; hg19: chr3-160952926; COSMIC: COSV63618348; COSMIC: COSV63618348;