16-14857598-C-T

Variant names:

• chr16-14857598-C-T
• rs757016366
• NM_014287.4:c.1163C>T

Variant summary

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

The NM_014287.4(NOMO1):​c.1163C>T​(p.Thr388Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,612,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: NOMO1 NM_014287.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.65

Genes affected

NOMO1 (HGNC:30060): (NODAL modulator 1) 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 region of duplication located on the p 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 (PXE). [provided by RefSeq, Jul 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=0.06965691).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOMO1	NM_014287.4	c.1163C>T	p.Thr388Met	missense_variant	Exon 11 of 31	ENST00000287667.12	NP_055102.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOMO1	ENST00000287667.12	c.1163C>T	p.Thr388Met	missense_variant	Exon 11 of 31	1	NM_014287.4	ENSP00000287667.7
NOMO1	ENST00000566883.5	n.455C>T		non_coding_transcript_exon_variant	Exon 5 of 6	4
NOMO1	ENST00000566917.1	n.*47C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000991 AC: 15 AN: 151294 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 251130 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135726

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461624 Hom.: 0 Cov.: 33 AF XY: 0.0000481 AC XY: 35 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000991 AC: 15 AN: 151294 Hom.: 0 Cov.: 27 AF XY: 0.000122 AC XY: 9 AN XY: 73806

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.000263

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1163C>T (p.T388M) alteration is located in exon 11 (coding exon 11) of the NOMO1 gene. This alteration results from a C to T substitution at nucleotide position 1163, causing the threonine (T) at amino acid position 388 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	0.070
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.017	T;T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.070	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.88	N;.;.
REVEL	Benign	0.079
Sift	Benign	0.12	T;.;.
Sift4G	Benign	0.12	T;T;T
Polyphen		0.023	B;.;.
Vest4		0.19
MutPred		0.29		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;
MVP		0.21
ClinPred		0.053	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.28

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: rs757016366; hg19: chr16-14951455; COSMIC: COSV55058744; COSMIC: COSV55058744;