12-89523004-G-T

Variant names:

• chr12-89523004-G-T
• rs139995124
• NM_003774.5:c.1546C>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.1546C>A​(p.Gln516Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00735 in 1,613,866 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0077 (60 hom.)
• Consequence: GALNT4 NM_003774.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.51
• Publications: 5 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=0.0054709613).
• BP6: Variant 12-89523004-G-T is Benign according to our data. Variant chr12-89523004-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 773664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 60 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.1546C>A	p.Gln516Lys	missense	Exon 1 of 1	NP_003765.2
	POC1B	NM_172240.3	MANE Select	c.100+2116C>A		intron	N/A	NP_758440.1	Q8TC44-1
	POC1B-GALNT4	NM_001199781.2		c.1537C>A	p.Gln513Lys	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.1546C>A	p.Gln516Lys	missense	Exon 1 of 1	ENSP00000436604.2	Q8N4A0-1
	POC1B-GALNT4	ENST00000548729.5	TSL:2	c.1537C>A	p.Gln513Lys	missense	Exon 3 of 3	ENSP00000447852.1	F8VUJ3
	POC1B	ENST00000313546.8	TSL:1 MANE Select	c.100+2116C>A		intron	N/A	ENSP00000323302.3	Q8TC44-1

Frequencies

GnomAD3 genomes AF: 0.00442 AC: 672 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00792

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00437 AC: 1087 AN: 249012 AF XY: 0.00428

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00488

Gnomad NFE exome AF: 0.00815

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00766 AC: 11190 AN: 1461566 Hom.: 60 Cov.: 30 AF XY: 0.00745 AC XY: 5414 AN XY: 727046

African (AFR) AF: 0.00105 AC: 35 AN: 33472

American (AMR) AF: 0.000336 AC: 15 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000568 AC: 49 AN: 86216

European-Finnish (FIN) AF: 0.00579 AC: 309 AN: 53402

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00947 AC: 10525 AN: 1111814

Other (OTH) AF: 0.00421 AC: 254 AN: 60372

GnomAD4 genome AF: 0.00441 AC: 672 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.00432 AC XY: 322 AN XY: 74468

African (AFR) AF: 0.00137 AC: 57 AN: 41570

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00546 AC: 58 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00792 AC: 539 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00641 Hom.: 6

Bravo AF: 0.00393

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00137 AC: 5

ESP6500EA AF: 0.00795 AC: 65

ExAC AF: 0.00422 AC: 510

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00694

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.065
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.080	N
PhyloP100		6.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.056
Sift	Benign	0.58	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.098
MVP		0.52
MPC		0.17
ClinPred		0.010	T
GERP RS		5.0
Varity_R		0.38
gMVP		0.44
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: rs139995124; hg19: chr12-89916781; COSMIC: COSV99046905; COSMIC: COSV99046905;