12-89523764-A-T

Position:

• chr12-89523764-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003774.5(GALNT4):​c.786T>A​(p.Asn262Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,539,628 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (17 hom.)
• Consequence: GALNT4 NM_003774.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.06

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008499026).
• BP6: Variant 12-89523764-A-T is Benign according to our data. Variant chr12-89523764-A-T is described in ClinVar as [Benign]. Clinvar id is 717686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNT4	NM_003774.5	c.786T>A	p.Asn262Lys	missense_variant	1/1	ENST00000529983.3	NP_003765.2
POC1B	NM_172240.3	c.100+1356T>A		intron_variant		ENST00000313546.8	NP_758440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNT4	ENST00000529983.3	c.786T>A	p.Asn262Lys	missense_variant	1/1	6	NM_003774.5	ENSP00000436604.2
POC1B-GALNT4	ENST00000548729.5	c.777T>A	p.Asn259Lys	missense_variant	3/3	2		ENSP00000447852.1
POC1B	ENST00000313546.8	c.100+1356T>A		intron_variant		1	NM_172240.3	ENSP00000323302.3

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 474 AN: 152208 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00385 AC: 696 AN: 180830 Hom.: 4 AF XY: 0.00403 AC XY: 385 AN XY: 95606

Gnomad AFR exome AF: 0.000612

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00234

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.00342

Gnomad OTH exome AF: 0.00530

GnomAD4 exome AF: 0.00342 AC: 4743 AN: 1387302 Hom.: 17 Cov.: 34 AF XY: 0.00331 AC XY: 2262 AN XY: 684174

Gnomad4 AFR exome AF: 0.000392

Gnomad4 AMR exome AF: 0.00164

Gnomad4 ASJ exome AF: 0.00289

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000837

Gnomad4 FIN exome AF: 0.0176

Gnomad4 NFE exome AF: 0.00326

Gnomad4 OTH exome AF: 0.00337

GnomAD4 genome AF: 0.00311 AC: 474 AN: 152326 Hom.: 2 Cov.: 32 AF XY: 0.00334 AC XY: 249 AN XY: 74500

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0173

Gnomad4 NFE AF: 0.00322

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00336 Hom.: 1

Bravo AF: 0.00189

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000264 AC: 1

ESP6500EA AF: 0.00377 AC: 31

ExAC AF: 0.00327 AC: 392

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0085	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.40	N;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.091
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.039	D;D
Polyphen		0.087	B;B
Vest4		0.20
MutPred		0.52		Gain of methylation at N262 (P = 0.0194);.;
MVP		0.46
MPC		0.23
ClinPred		0.050	T
GERP RS		-3.9
Varity_R		0.53
gMVP		0.72

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: rs188465081; hg19: chr12-89917541;