1-100877863-T-C

Variant names:

• chr1-100877863-T-C
• rs980884530
• NM_001033025.3:c.46A>G

Variant summary

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

The NM_001033025.3(EXTL2):​c.46A>G​(p.Ile16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXTL2 NM_001033025.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.770

Genes affected

EXTL2 (HGNC:3516): (exostosin like glycosyltransferase 2) Enables alpha-1,4-N-acetylgalactosaminyltransferase activity and glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity. Involved in N-acetylglucosamine metabolic process and UDP-N-acetylgalactosamine metabolic process. Located in cytosol; endoplasmic reticulum; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.08893132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXTL2	NM_001033025.3	c.46A>G	p.Ile16Val	missense_variant	Exon 3 of 5	ENST00000370114.8	NP_001028197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXTL2	ENST00000370114.8	c.46A>G	p.Ile16Val	missense_variant	Exon 3 of 5	1	NM_001033025.3	ENSP00000359132.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46A>G (p.I16V) alteration is located in exon 3 (coding exon 2) of the EXTL2 gene. This alteration results from a A to G substitution at nucleotide position 46, causing the isoleucine (I) at amino acid position 16 to be replaced by a valine (V). 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	0.079
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.091	.;T;T;T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.66	T;.;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.089	T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	2.0	.;M;M;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.21	.;N;N;N;N
REVEL	Benign	0.094
Sift	Uncertain	0.010	.;D;D;T;D
Sift4G	Benign	0.17	T;T;T;.;T
Polyphen		0.0	.;B;B;.;.
Vest4		0.12
MutPred		0.21		Loss of catalytic residue at L21 (P = 0.0464);Loss of catalytic residue at L21 (P = 0.0464);Loss of catalytic residue at L21 (P = 0.0464);.;.;
MVP		0.40
MPC		0.15
ClinPred		0.11	T
GERP RS		3.1
Varity_R		0.026
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs980884530; hg19: chr1-101343419;