16-14857566-C-G

Variant names:

• chr16-14857566-C-G
• rs1268158290
• NM_014287.4:c.1131C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014287.4(NOMO1):​c.1131C>G​(p.Ile377Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,611,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: NOMO1 NM_014287.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014287.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOMO1	NM_014287.4	MANE Select	c.1131C>G	p.Ile377Met	missense	Exon 11 of 31	NP_055102.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOMO1	ENST00000287667.12	TSL:1 MANE Select	c.1131C>G	p.Ile377Met	missense	Exon 11 of 31	ENSP00000287667.7	Q15155
	NOMO1	ENST00000880310.1		c.1131C>G	p.Ile377Met	missense	Exon 11 of 31	ENSP00000550369.1
	NOMO1	ENST00000924494.1		c.1131C>G	p.Ile377Met	missense	Exon 11 of 31	ENSP00000594553.1

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 4 AN: 150330 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000490

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250948 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461602 Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15 AN XY: 727116

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111810

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome AF: 0.0000266 AC: 4 AN: 150330 Hom.: 0 Cov.: 27 AF XY: 0.0000410 AC XY: 3 AN XY: 73224

African (AFR) AF: 0.0000490 AC: 2 AN: 40782

American (AMR) AF: 0.00 AC: 0 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67468

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.1
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.024	D
Polyphen		0.81	P
Vest4		0.91
MutPred		0.60		Loss of sheet (P = 0.0126)
MVP		0.22
ClinPred		0.66	D
GERP RS		2.1
Varity_R		0.25
gMVP		0.46
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs1268158290; hg19: chr16-14951423;