12-101770185-A-T

Variant names:

• chr12-101770185-A-T
• rs137852900
• NM_024312.5:c.1120T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_024312.5(GNPTAB):​c.1120T>A​(p.Phe374Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F374L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNPTAB NM_024312.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.72
• Publications: 0 publications found

Genes affected

GNPTAB (HGNC:29670): (N-acetylglucosamine-1-phosphate transferase subunits alpha and beta) This gene encodes two of three subunit types of the membrane-bound enzyme N-acetylglucosamine-1-phosphotransferase, a heterohexameric complex composed of two alpha, two beta, and two gamma subunits. The encoded protein is proteolytically cleaved at the Lys928-Asp929 bond to yield mature alpha and beta polypeptides while the gamma subunits are the product of a distinct gene (GeneID 84572). In the Golgi apparatus, the heterohexameric complex catalyzes the first step in the synthesis of mannose 6-phosphate recognition markers on certain oligosaccharides of newly synthesized lysosomal enzymes. These recognition markers are essential for appropriate trafficking of lysosomal enzymes. Mutations in this gene have been associated with both mucolipidosis II and mucolipidosis IIIA.[provided by RefSeq, May 2010]

GNPTAB Gene-Disease associations (from GenCC):

• GNPTAB-mucolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mucolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• mucolipidosis type II

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• mucolipidosis type III, alpha/beta

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_024312.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-101770185-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2775.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.1120T>A	p.Phe374Ile	missense_variant	Exon 10 of 21	ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3	c.1039T>A	p.Phe347Ile	missense_variant	Exon 10 of 21		XP_011537033.1
GNPTAB	XM_006719593.4	c.1120T>A	p.Phe374Ile	missense_variant	Exon 10 of 19		XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.1120T>A	p.Phe374Ile	missense_variant	Exon 10 of 21	1	NM_024312.5	ENSP00000299314.7
GNPTAB	ENST00000549940.5	c.1120T>A	p.Phe374Ile	missense_variant	Exon 10 of 11	1		ENSP00000449150.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.7	L;L
PhyloP100		8.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.0030	D;T
Polyphen		0.97	D;P
Vest4		0.83
MutPred		0.56		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.91
MPC		0.94
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.68
gMVP		0.89
Mutation Taster		=23/77	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: rs137852900; hg19: chr12-102163963;