NM_030769.3:c.664T>C

Variant names:

• chr1-182822125-T-C
• rs753930468
• NM_030769.3:c.664T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030769.3(NPL):​c.664T>C​(p.Tyr222His) variant causes a missense change. The variant allele was found at a frequency of 0.00000617 in 1,458,934 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: NPL NM_030769.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82
• Publications: 0 publications found

Genes affected

NPL (HGNC:16781): (N-acetylneuraminate pyruvate lyase) This gene encodes a member of the N-acetylneuraminate lyase sub-family of (beta/alpha)(8)-barrel enzymes. N-acetylneuraminate lyases regulate cellular concentrations of N-acetyl-neuraminic acid (sialic acid) by mediating the reversible conversion of sialic acid into N-acetylmannosamine and pyruvate. A pseudogene of this gene is located on the short arm of chromosome 2. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030769.3. 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
	NPL	NM_030769.3	MANE Select	c.664T>C	p.Tyr222His	missense	Exon 11 of 13	NP_110396.1	Q9BXD5-1
	NPL	NM_001200050.2		c.607T>C	p.Tyr203His	missense	Exon 9 of 11	NP_001186979.1	Q9BXD5-2
	NPL	NM_001200056.2		c.664T>C	p.Tyr222His	missense	Exon 11 of 13	NP_001186985.1	Q9BXD5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPL	ENST00000367553.6	TSL:1 MANE Select	c.664T>C	p.Tyr222His	missense	Exon 11 of 13	ENSP00000356524.1	Q9BXD5-1
	NPL	ENST00000258317.6	TSL:1	c.664T>C	p.Tyr222His	missense	Exon 9 of 11	ENSP00000258317.2	Q9BXD5-1
	NPL	ENST00000367554.7	TSL:1	c.607T>C	p.Tyr203His	missense	Exon 9 of 11	ENSP00000356525.3	Q9BXD5-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251426 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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458934 Hom.: 0 Cov.: 29 AF XY: 0.00000689 AC XY: 5 AN XY: 726092

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109326

Other (OTH) AF: 0.0000166 AC: 1 AN: 60298

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

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	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.050	T
Polyphen		1.0	D
Vest4		0.90
MutPred		0.84		Gain of disorder (P = 0.023)
MVP		0.91
MPC		0.68
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.86
gMVP		0.91
Mutation Taster		=47/53	disease causing

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: rs753930468; hg19: chr1-182791260;