chr12-89523034-C-T

Variant names:

• chr12-89523034-C-T
• rs2230283
• NM_003774.5:c.1516G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003774.5(GALNT4):​c.1516G>A​(p.Val506Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,613,338 control chromosomes in the GnomAD database, including 84,836 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.28 (6488 hom., cov: 32)
  • Exomes 𝑓: 0.32 (78348 hom.)
• Consequence: GALNT4 NM_003774.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51
• Publications: 38 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016531348).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

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.1516G>A	p.Val506Ile	missense	Exon 1 of 1	NP_003765.2
	POC1B	NM_172240.3	MANE Select	c.100+2086G>A		intron	N/A	NP_758440.1	Q8TC44-1
	POC1B-GALNT4	NM_001199781.2		c.1507G>A	p.Val503Ile	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.1516G>A	p.Val506Ile	missense	Exon 1 of 1	ENSP00000436604.2	Q8N4A0-1
	POC1B-GALNT4	ENST00000548729.5	TSL:2	c.1507G>A	p.Val503Ile	missense	Exon 3 of 3	ENSP00000447852.1	F8VUJ3
	POC1B	ENST00000313546.8	TSL:1 MANE Select	c.100+2086G>A		intron	N/A	ENSP00000323302.3	Q8TC44-1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42573 AN: 151968 Hom.: 6487 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.287

GnomAD2 exomes AF: 0.278 AC: 68996 AN: 248526 AF XY: 0.276

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.216

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.137

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.298

GnomAD4 exome AF: 0.321 AC: 469391 AN: 1461250 Hom.: 78348 Cov.: 41 AF XY: 0.317 AC XY: 230737 AN XY: 726866

African (AFR) AF: 0.186 AC: 6232 AN: 33470

American (AMR) AF: 0.223 AC: 9981 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 8012 AN: 26126

East Asian (EAS) AF: 0.157 AC: 6225 AN: 39696

South Asian (SAS) AF: 0.181 AC: 15639 AN: 86212

European-Finnish (FIN) AF: 0.339 AC: 18110 AN: 53390

Middle Eastern (MID) AF: 0.243 AC: 1403 AN: 5768

European-Non Finnish (NFE) AF: 0.347 AC: 385372 AN: 1111544

Other (OTH) AF: 0.305 AC: 18417 AN: 60364

GnomAD4 genome AF: 0.280 AC: 42591 AN: 152088 Hom.: 6488 Cov.: 32 AF XY: 0.276 AC XY: 20536 AN XY: 74336

African (AFR) AF: 0.180 AC: 7486 AN: 41474

American (AMR) AF: 0.271 AC: 4145 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1049 AN: 3466

East Asian (EAS) AF: 0.137 AC: 711 AN: 5180

South Asian (SAS) AF: 0.181 AC: 871 AN: 4824

European-Finnish (FIN) AF: 0.333 AC: 3518 AN: 10566

Middle Eastern (MID) AF: 0.257 AC: 75 AN: 292

European-Non Finnish (NFE) AF: 0.348 AC: 23665 AN: 67986

Other (OTH) AF: 0.289 AC: 609 AN: 2110

Alfa AF: 0.319 Hom.: 37555

Bravo AF: 0.268

TwinsUK AF: 0.352 AC: 1307

ALSPAC AF: 0.358 AC: 1378

ESP6500AA AF: 0.179 AC: 657

ESP6500EA AF: 0.343 AC: 2808

ExAC AF: 0.277 AC: 33402

Asia WGS AF: 0.215 AC: 749 AN: 3478

EpiCase AF: 0.343

EpiControl AF: 0.340

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.21
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.076	T
Polyphen		0.88	P
Vest4		0.12
MPC		0.48
ClinPred		0.051	T
GERP RS		5.9
Varity_R		0.60
gMVP		0.37
Mutation Taster		=53/47	polymorphism (auto)

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: rs2230283; hg19: chr12-89916811; COSMIC: COSV57962819; COSMIC: COSV57962819;