3-161235144-A-G

Position:

• chr3-161235144-A-G

Variant summary

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

The NM_015938.5(NMD3):​c.509A>G​(p.Tyr170Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000291 in 1,375,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: NMD3 NM_015938.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59

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]

NMD3 (HGNC:):

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, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NMD3	NM_015938.5	c.509A>G	p.Tyr170Cys	missense_variant	7/16	ENST00000351193.7	NP_057022.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NMD3	ENST00000351193.7	c.509A>G	p.Tyr170Cys	missense_variant	7/16	1	NM_015938.5	ENSP00000307525.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000291 AC: 4 AN: 1375256 Hom.: 0 Cov.: 21 AF XY: 0.00000146 AC XY: 1 AN XY: 687248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000286

Gnomad4 OTH exome AF: 0.0000175

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

Oct 07, 2024

The c.509A>G (p.Y170C) alteration is located in exon 7 (coding exon 6) of the NMD3 gene. This alteration results from a A to G substitution at nucleotide position 509, causing the tyrosine (Y) at amino acid position 170 to be replaced by a cysteine (C). 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	Uncertain	0.37
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;.;T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.5	.;M;.;.;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.7	D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.;D
Vest4		0.85, 0.87
MutPred		0.83		Loss of MoRF binding (P = 0.0884);Loss of MoRF binding (P = 0.0884);Loss of MoRF binding (P = 0.0884);Loss of MoRF binding (P = 0.0884);Loss of MoRF binding (P = 0.0884);
MVP		0.62
MPC		0.47
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.75
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs1736708550; hg19: chr3-160952932;