12-4765380-A-T

Variant names:

• chr12-4765380-A-T
• rs1946394691
• NM_017417.2:c.1595A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_017417.2(GALNT8):​c.1595A>T​(p.Asn532Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N532T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GALNT8 NM_017417.2 missense, splice_region
• Scores: Splicing: ADA: 0.0008425
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49
• Publications: 0 publications found

Genes affected

GALNT8 (HGNC:4130): (polypeptide N-acetylgalactosaminyltransferase 8) 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. [provided by RefSeq, Jul 2008]

ENSG00000255639 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14386493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNT8	NM_017417.2	c.1595A>T	p.Asn532Ile	missense_variant, splice_region_variant	Exon 10 of 11	ENST00000252318.7	NP_059113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALNT8	ENST00000252318.7	c.1595A>T	p.Asn532Ile	missense_variant, splice_region_variant	Exon 10 of 11	1	NM_017417.2	ENSP00000252318.2
ENSG00000255639	ENST00000648836.1	c.1385A>T	p.Asn462Ile	missense_variant, splice_region_variant	Exon 14 of 15			ENSP00000497305.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 113812 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000238 AC: 2 AN: 838696 Hom.: 0 Cov.: 20 AF XY: 0.00000468 AC XY: 2 AN XY: 427312

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000529 AC: 1 AN: 18888

American (AMR) AF: 0.00 AC: 0 AN: 23392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16562

East Asian (EAS) AF: 0.00 AC: 0 AN: 30950

South Asian (SAS) AF: 0.00 AC: 0 AN: 57234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2602

European-Non Finnish (NFE) AF: 0.00000165 AC: 1 AN: 605774

Other (OTH) AF: 0.00 AC: 0 AN: 37362

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 113870 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 52404

African (AFR) AF: 0.00 AC: 0 AN: 29550

American (AMR) AF: 0.00 AC: 0 AN: 9198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3096

East Asian (EAS) AF: 0.00 AC: 0 AN: 3608

South Asian (SAS) AF: 0.00 AC: 0 AN: 3390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 174

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 58666

Other (OTH) AF: 0.00 AC: 0 AN: 1500

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.89
DEOGEN2	Benign	0.018	.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.17	T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	.;M
PhyloP100		1.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	.;D
REVEL	Benign	0.19
Sift	Benign	0.37	.;T
Sift4G	Benign	0.39	.;T
Polyphen		0.038	.;B
Vest4		0.40
MutPred		0.56		.;Loss of sheet (P = 0.0315);
MVP		0.11
MPC		0.14
ClinPred		0.14	T
GERP RS		2.8
Varity_R		0.27
gMVP		0.38
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00084
dbscSNV1_RF	Benign	0.0060
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: rs1946394691; hg19: chr12-4874546;