1-100874247-G-A

Variant names:

• chr1-100874247-G-A
• rs1648924366
• NM_001033025.3:c.688C>T

Variant summary

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

The NM_001033025.3(EXTL2):​c.688C>T​(p.Pro230Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EXTL2 NM_001033025.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.76

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 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, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXTL2	NM_001033025.3	c.688C>T	p.Pro230Ser	missense_variant	Exon 5 of 5	ENST00000370114.8	NP_001028197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXTL2	ENST00000370114.8	c.688C>T	p.Pro230Ser	missense_variant	Exon 5 of 5	1	NM_001033025.3	ENSP00000359132.3
EXTL2	ENST00000370113.7	c.688C>T	p.Pro230Ser	missense_variant	Exon 5 of 5	1		ENSP00000359131.3
EXTL2	ENST00000450240.2	c.712C>T	p.Pro238Ser	missense_variant	Exon 6 of 6	4		ENSP00000403363.1
EXTL2	ENST00000535414	c.*173C>T		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000444385.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460682 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.688C>T (p.P230S) alteration is located in exon 5 (coding exon 4) of the EXTL2 gene. This alteration results from a C to T substitution at nucleotide position 688, causing the proline (P) at amino acid position 230 to be replaced by a serine (S). 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	0.23
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;D;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Uncertain	2.9	M;M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.2	D;D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.052	T;T;D
Sift4G	Benign	0.12	T;T;.
Polyphen		0.96	D;D;.
Vest4		0.60
MutPred		0.85		Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);.;
MVP		0.93
MPC		0.60
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.50
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1648924366; hg19: chr1-101339803;