12-4744540-G-A

Position:

• chr12-4744540-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_017417.2(GALNT8):​c.700G>A​(p.Glu234Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000883 in 1,610,838 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0046 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (4 hom.)
• Consequence: GALNT8 NM_017417.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.159

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033804178).
• BP6: Variant 12-4744540-G-A is Benign according to our data. Variant chr12-4744540-G-A is described in ClinVar as [Benign]. Clinvar id is 784228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALNT8	NM_017417.2	c.700G>A	p.Glu234Lys	missense_variant	4/11	ENST00000252318.7	NP_059113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALNT8	ENST00000252318.7	c.700G>A	p.Glu234Lys	missense_variant	4/11	1	NM_017417.2	ENSP00000252318.2
ENSG00000255639	ENST00000648836.1	c.964-16418G>A		intron_variant				ENSP00000497305.1
ENSG00000255639	ENST00000544741.2	n.*477G>A		non_coding_transcript_exon_variant	6/6	3		ENSP00000456318.2
ENSG00000255639	ENST00000544741.2	n.*477G>A		3_prime_UTR_variant	6/6	3		ENSP00000456318.2

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 695 AN: 152166 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.000118

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00120 AC: 298 AN: 248804 Hom.: 2 AF XY: 0.000996 AC XY: 134 AN XY: 134548

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.000914

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000496 AC: 724 AN: 1458554 Hom.: 4 Cov.: 29 AF XY: 0.000478 AC XY: 347 AN XY: 725650

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.000925

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000816

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000856

Gnomad4 OTH exome AF: 0.000896

GnomAD4 genome AF: 0.00459 AC: 699 AN: 152284 Hom.: 10 Cov.: 32 AF XY: 0.00418 AC XY: 311 AN XY: 74458

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000913 Hom.: 0

Bravo AF: 0.00476

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00161 AC: 195

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000110

EpiControl AF: 0.0000596

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.037
Sift	Benign	0.30	T
Sift4G	Benign	0.23	T
Polyphen		0.15	B
Vest4		0.12
MVP		0.12
MPC		0.13
ClinPred		0.0082	T
GERP RS		-0.92
Varity_R		0.18
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs16931676; hg19: chr12-4853706;