6-149727066-C-A

Variant names:

• chr6-149727066-C-A
• rs932467155
• NM_198887.3:c.1046G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198887.3(NUP43):​c.1046G>T​(p.Arg349Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUP43 NM_198887.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

Genes affected

NUP43 (HGNC:21182): (nucleoporin 43) Bidirectional transport of macromolecules between the cytoplasm and nucleus occurs through nuclear pore complexes (NPCs) embedded in the nuclear envelope. NPCs are composed of subcomplexes, and NUP43 is part of one such subcomplex, Nup107-160 (Loiodice et al., 2004 [PubMed 15146057]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14049575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUP43	NM_198887.3	c.1046G>T	p.Arg349Met	missense_variant	Exon 8 of 8	ENST00000340413.7	NP_942590.1
NUP43	XM_047418728.1	c.1046G>T	p.Arg349Met	missense_variant	Exon 9 of 9		XP_047274684.1
NUP43	XM_005266960.6	c.*1324G>T		3_prime_UTR_variant	Exon 8 of 8		XP_005267017.1
NUP43	NR_104456.2	n.1080G>T		non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUP43	ENST00000340413.7	c.1046G>T	p.Arg349Met	missense_variant	Exon 8 of 8	1	NM_198887.3	ENSP00000342262.2
NUP43	ENST00000367404.8	c.758G>T	p.Arg253Met	missense_variant	Exon 6 of 6	2		ENSP00000356374.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1046G>T (p.R349M) alteration is located in exon 8 (coding exon 8) of the NUP43 gene. This alteration results from a G to T substitution at nucleotide position 1046, causing the arginine (R) at amino acid position 349 to be replaced by a methionine (M). 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	Benign	0.22
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.010	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.085
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.73	N;N
REVEL	Benign	0.093
Sift	Benign	0.049	D;T
Sift4G	Benign	0.12	T;T
Polyphen		0.91	P;.
Vest4		0.20
MutPred		0.43		Loss of catalytic residue at R349 (P = 0.0277);.;
MVP		0.70
MPC		0.14
ClinPred		0.51	D
GERP RS		4.0
Varity_R		0.15
gMVP		0.32

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: rs932467155; hg19: chr6-150048202; COSMIC: COSV100462302; COSMIC: COSV100462302;