chr16-14846618-G-C

Variant names:

• chr16-14846618-G-C
• rs568175211
• NM_014287.4:c.444G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014287.4(NOMO1):​c.444G>C​(p.Gln148His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOMO1 NM_014287.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22389063).

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.444G>C	p.Gln148His	missense	Exon 5 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.444G>C	p.Gln148His	missense	Exon 5 of 31	ENSP00000287667.7	Q15155
	NOMO1	ENST00000880310.1		c.444G>C	p.Gln148His	missense	Exon 5 of 31	ENSP00000550369.1
	NOMO1	ENST00000924494.1		c.444G>C	p.Gln148His	missense	Exon 5 of 31	ENSP00000594553.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD2 exomes AF: 0.00000529 AC: 1 AN: 189182 AF XY: 0.00000978

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000663

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.34e-7 AC: 1 AN: 1198812 Hom.: 0 Cov.: 16 AF XY: 0.00000167 AC XY: 1 AN XY: 600532

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27838

American (AMR) AF: 0.00 AC: 0 AN: 37162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22480

East Asian (EAS) AF: 0.0000271 AC: 1 AN: 36926

South Asian (SAS) AF: 0.00 AC: 0 AN: 74404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3558

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 894750

Other (OTH) AF: 0.00 AC: 0 AN: 51276

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 19

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	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.058
Sift	Benign	0.092	T
Sift4G	Uncertain	0.060	T
Polyphen		0.69	P
Vest4		0.45
MutPred		0.43		Gain of methylation at R152 (P = 0.1065)
MVP		0.25
ClinPred		0.29	T
GERP RS		-0.15
Varity_R		0.057
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs568175211; hg19: chr16-14940475;