16-10769049-A-T

Variant names:

• chr16-10769049-A-T
• rs749394368
• NM_002484.4:c.907A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002484.4(NUBP1):​c.907A>T​(p.Ile303Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NUBP1 NM_002484.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

Genes affected

NUBP1 (HGNC:8041): (NUBP iron-sulfur cluster assembly factor 1, cytosolic) NUBP1 is a member of the NUBP/MRP subfamily of ATP-binding proteins (Nakashima et al., 1999 [PubMed 10486206]).[supplied by OMIM, Mar 2008]

TVP23A (HGNC:20398): (trans-golgi network vesicle protein 23 homolog A) This gene encodes a membrane protein associated with the Golgi apparatus, which plays a crucial role in intracellular vesicular transport. The encoded protein is likely associated with the late (trans) Golgi compartments, which are involved in the delivery of secretory and membrane proteins to the endosome, lysosome or the plasma membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2787336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUBP1	NM_002484.4	c.907A>T	p.Ile303Phe	missense_variant, splice_region_variant	Exon 11 of 11	ENST00000283027.10	NP_002475.2
TVP23A	NM_001079512.4	c.*53T>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000299866.13	NP_001072980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUBP1	ENST00000283027.10	c.907A>T	p.Ile303Phe	missense_variant, splice_region_variant	Exon 11 of 11	1	NM_002484.4	ENSP00000283027.5
TVP23A	ENST00000299866	c.*53T>A		3_prime_UTR_variant	Exon 8 of 8	2	NM_001079512.4	ENSP00000299866.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251470 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461832 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

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.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.907A>T (p.I303F) alteration is located in exon 11 (coding exon 11) of the NUBP1 gene. This alteration results from a A to T substitution at nucleotide position 907, causing the isoleucine (I) at amino acid position 303 to be replaced by a phenylalanine (F). 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	0.43
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	0.041
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.21
Sift	Benign	0.040	D;D
Sift4G	Uncertain	0.035	D;D
Polyphen		0.026	B;B
Vest4		0.62
MutPred		0.47		Gain of helix (P = 0.0696);.;
MVP		0.35
MPC		0.11
ClinPred		0.86	D
GERP RS		4.9
Varity_R		0.29
gMVP		0.88

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: rs749394368; hg19: chr16-10862906;