chr9-127890940-C-A

Position:

• chr9-127890940-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_013443.5(ST6GALNAC6):​c.401G>T​(p.Arg134Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ST6GALNAC6 NM_013443.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45

Genes affected

ST6GALNAC6 (HGNC:23364): (ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 6) ST6GALNAC6 belongs to a family of sialyltransferases that modify proteins and ceramides on the cell surface to alter cell-cell or cell-extracellular matrix interactions (Tsuchida et al., 2003 [PubMed 12668675]).[supplied by OMIM, Mar 2008]

ST6GALNAC4-ST6GALNAC6-AK1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ST6GALNAC6	NM_013443.5	c.401G>T	p.Arg134Leu	missense_variant	5/7	ENST00000373146.6	NP_038471.2
ST6GALNAC4-ST6GALNAC6-AK1	NR_174625.1	n.1277G>T		non_coding_transcript_exon_variant	7/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ST6GALNAC6	ENST00000373146.6	c.401G>T	p.Arg134Leu	missense_variant	5/7	1	NM_013443.5	ENSP00000362239

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

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

Oct 30, 2023

The c.401G>T (p.R134L) alteration is located in exon 5 (coding exon 4) of the ST6GALNAC6 gene. This alteration results from a G to T substitution at nucleotide position 401, causing the arginine (R) at amino acid position 134 to be replaced by a leucine (L). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T;.;.;.;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;.;D;.;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.7	H;H;.;.;H;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.7	D;D;.;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;.;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;.
Polyphen		1.0	D;D;D;D;.;D;.
Vest4		0.99
MutPred		0.89		Loss of phosphorylation at T132 (P = 0.0735);Loss of phosphorylation at T132 (P = 0.0735);.;.;Loss of phosphorylation at T132 (P = 0.0735);.;.;
MVP		0.89
MPC		1.4
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.87
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200500949; hg19: chr9-130653219;