chr12-4726730-A-G

Position:

• chr12-4726730-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017417.2(GALNT8):​c.410A>G​(p.Gln137Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000146 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: GALNT8 NM_017417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09383997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNT8	NM_017417.2	c.410A>G	p.Gln137Arg	missense_variant	2/11	ENST00000252318.7	NP_059113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNT8	ENST00000252318.7	c.410A>G	p.Gln137Arg	missense_variant	2/11	1	NM_017417.2	ENSP00000252318.2
ENSG00000255639	ENST00000648836.1	c.964-34228A>G		intron_variant				ENSP00000497305.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251370 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135866

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000144 AC: 211 AN: 1461832 Hom.: 0 Cov.: 33 AF XY: 0.000142 AC XY: 103 AN XY: 727226

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152274 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74454

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2021

The c.410A>G (p.Q137R) alteration is located in exon 2 (coding exon 2) of the GALNT8 gene. This alteration results from a A to G substitution at nucleotide position 410, causing the glutamine (Q) at amino acid position 137 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0038	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.72	N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.096
Sift	Benign	0.28	T
Sift4G	Benign	0.45	T
Polyphen		1.0	D
Vest4		0.27
MVP		0.20
MPC		0.40
ClinPred		0.28	T
GERP RS		4.0
Varity_R		0.19
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs141779145; hg19: chr12-4835896;