12-89523356-G-A

Position:

• chr12-89523356-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_003774.5(GALNT4):​c.1194C>T​(p.Asn398Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000479 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GALNT4 NM_003774.5 synonymous
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.85

Genes affected

GALNT4 (HGNC:4126): (polypeptide N-acetylgalactosaminyltransferase 4) This gene encodes a member of the UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase (GalNAc-T) family of enzymes. GalNAc-Ts initiate mucin-type O-linked glycosylation in the Golgi apparatus by catalyzing the transfer of GalNAc to serine and threonine residues on target proteins. They are characterized by an N-terminal transmembrane domain, a stem region, a lumenal catalytic domain containing a GT1 motif and Gal/GalNAc transferase motif, and a C-terminal ricin/lectin-like domain. GalNAc-Ts have different, but overlapping, substrate specificities and patterns of expression. In vitro, the encoded protein can complement other GalNAc-Ts in the complete O-glycosylation of the mucin-1 tandem repeat and can O-glycosylate the P-selectin glycoprotein ligand-1 molecule. The coding region of this gene is contained within a single exon. Fusion transcripts, which combine part of this gene with the 5' exons of the neighboring POC1B (POC1 centriolar protein homolog B) gene, also exist. [provided by RefSeq, Dec 2010]

POC1B-GALNT4 (HGNC:42957): (POC1B-GALNT4 readthrough) This locus represents naturally occurring transcripts that splice the 5' exons of the POC1B (POC1 centriolar protein homolog B) gene on chromosome 12 to the GALNT4 (UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 4) gene, which is located within a POC1B intron. Alternative splicing results in two transcript variants, one of which encodes a fusion isoform that shares sequence identity with the products of each individual gene. [provided by RefSeq, Dec 2010]

POC1B (HGNC:30836): (POC1 centriolar protein B) POC1 proteins contain an N-terminal WD40 domain and a C-terminal coiled coil domain and are part of centrosomes. They play an important role in basal body and cilia formation. This gene encodes one of the two POC1 proteins found in humans. Mutation in this gene result in autosomal-recessive cone-rod dystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

POC1B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-89523356-G-A is Pathogenic according to our data. Variant chr12-89523356-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208386.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNT4	NM_003774.5	c.1194C>T	p.Asn398Asn	synonymous_variant	1/1	ENST00000529983.3	NP_003765.2
POC1B	NM_172240.3	c.100+1764C>T		intron_variant		ENST00000313546.8	NP_758440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNT4	ENST00000529983.3	c.1194C>T	p.Asn398Asn	synonymous_variant	1/1	6	NM_003774.5	ENSP00000436604.2
POC1B-GALNT4	ENST00000548729.5	c.1185C>T	p.Asn395Asn	synonymous_variant	3/3	2		ENSP00000447852.1
POC1B	ENST00000313546.8	c.100+1764C>T		intron_variant		1	NM_172240.3	ENSP00000323302.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249242 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461706 Hom.: 0 Cov.: 88 AF XY: 0.00000275 AC XY: 2 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Childhood-onset schizophrenia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Dr. Guy Rouleau's laboratory, McGill University

Jan 01, 2014

COS with Generalized Anxiety Disorder -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.4
DANN	Benign	0.87

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: rs863223348; hg19: chr12-89917133;