chr12-89523764-A-T

Variant names:

• chr12-89523764-A-T
• rs188465081
• NM_003774.5:c.786T>A

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• cone-rod dystrophy 20

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

POC1B-DUSP6 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 717686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003774.5. 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
	GALNT4	NM_003774.5	MANE Select	c.786T>A	p.Asn262Lys	missense	Exon 1 of 1	NP_003765.2
	POC1B	NM_172240.3	MANE Select	c.100+1356T>A		intron	N/A	NP_758440.1	Q8TC44-1
	POC1B-GALNT4	NM_001199781.2		c.777T>A	p.Asn259Lys	missense	Exon 3 of 3	NP_001186710.1	F8VUJ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALNT4	ENST00000529983.3	TSL:6 MANE Select	c.786T>A	p.Asn262Lys	missense	Exon 1 of 1	ENSP00000436604.2	Q8N4A0-1
	POC1B-GALNT4	ENST00000548729.5	TSL:2	c.777T>A	p.Asn259Lys	missense	Exon 3 of 3	ENSP00000447852.1	F8VUJ3
	POC1B	ENST00000313546.8	TSL:1 MANE Select	c.100+1356T>A		intron	N/A	ENSP00000323302.3	Q8TC44-1

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

GnomAD2 exomes AF: 0.00385 AC: 696 AN: 180830 AF XY: 0.00403

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 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

African (AFR) AF: 0.000392 AC: 12 AN: 30614

American (AMR) AF: 0.00164 AC: 50 AN: 30556

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 59 AN: 20398

East Asian (EAS) AF: 0.00 AC: 0 AN: 39334

South Asian (SAS) AF: 0.0000837 AC: 6 AN: 71708

European-Finnish (FIN) AF: 0.0176 AC: 890 AN: 50436

Middle Eastern (MID) AF: 0.000742 AC: 4 AN: 5388

European-Non Finnish (NFE) AF: 0.00326 AC: 3529 AN: 1081678

Other (OTH) AF: 0.00337 AC: 193 AN: 57190

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

African (AFR) AF: 0.000409 AC: 17 AN: 41574

American (AMR) AF: 0.00235 AC: 36 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0173 AC: 184 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00322 AC: 219 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.40	N
PhyloP100		1.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.091
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.039	D
Polyphen		0.087	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
Mutation Taster		=33/67	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: rs188465081; hg19: chr12-89917541;