16-16256008-T-C

Variant names:

• chr16-16256008-T-C
• rs973401954
• NM_001004067.4:c.1070T>C

Variant summary

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

The NM_001004067.4(NOMO3):​c.1070T>C​(p.Val357Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000736 in 135,938 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V357D) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000074 (0 hom., cov: 21)
• Consequence: NOMO3 NM_001004067.4 missense, splice_region
• Scores: Splicing: ADA: 0.0006461
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15

Genes affected

NOMO3 (HGNC:25242): (NODAL modulator 3) This gene encodes a protein originally thought to be related to the collagenase gene family. This gene is one of three highly similar genes in a duplicated region on the short arm of chromosome 16. These three genes encode closely related proteins that may have the same function. The protein encoded by one of these genes has been identified as part of a protein complex that participates in the Nodal signaling pathway during vertebrate development. Mutations in ABCC6, which is located nearby, rather than mutations in this gene are associated with pseudoxanthoma elasticum. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOMO3	NM_001004067.4	c.1070T>C	p.Val357Ala	missense_variant, splice_region_variant	Exon 11 of 31	ENST00000399336.9	NP_001004067.1
NOMO3	XM_005255318.2	c.1070T>C	p.Val357Ala	missense_variant, splice_region_variant	Exon 11 of 32		XP_005255375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOMO3	ENST00000399336.9	c.1070T>C	p.Val357Ala	missense_variant, splice_region_variant	Exon 11 of 31	1	NM_001004067.4	ENSP00000382274.4

Frequencies

GnomAD3 genomes AF: 0.00000736 AC: 1 AN: 135938 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000736 AC: 1 AN: 135938 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 65946

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1070T>C (p.V357A) alteration is located in exon 11 (coding exon 11) of the NOMO3 gene. This alteration results from a T to C substitution at nucleotide position 1070, causing the valine (V) at amino acid position 357 to be replaced by an alanine (A). 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	0.32
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.0020	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.72	N;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.84	N;N
REVEL	Benign	0.17
Sift	Benign	0.61	T;T
Sift4G	Uncertain	0.048	D;D
Polyphen		0.0040	B;.
Vest4		0.74
MutPred		0.71		Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP		0.20
ClinPred		0.70	D
GERP RS		3.3
Varity_R		0.041
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00065
dbscSNV1_RF	Benign	0.018
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: rs973401954; hg19: chr16-16349865;