Variant 1-100876805-A-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001033025.3(EXTL2):c.493T>G(p.Ser165Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000993 in 1,611,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

EXTL2
NM_001033025.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.30

Variant links:

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]

EXTL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXTL2	NM_001033025.3 linkuse as main transcript	c.493T>G	p.Ser165Ala	missense_variant	4/5	ENST00000370114.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
EXTL2	ENST00000370114.8 linkuse as main transcript	c.493T>G	p.Ser165Ala	missense_variant	4/5	1	NM_001033025.3	P1
EXTL2	ENST00000370113.7 linkuse as main transcript	c.493T>G	p.Ser165Ala	missense_variant	4/5	1		P1
EXTL2	ENST00000450240.2 linkuse as main transcript	c.517T>G	p.Ser173Ala	missense_variant	5/6	4
EXTL2	ENST00000535414.5 linkuse as main transcript	c.433+671T>G		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1459686

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726236

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.493T>G (p.S165A) alteration is located in exon 4 (coding exon 3) of the EXTL2 gene. This alteration results from a T to G substitution at nucleotide position 493, causing the serine (S) at amino acid position 165 to be replaced by an alanine (A). 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

0.11

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

1.0

M_CAP

Benign

0.053

MetaRNN

Uncertain

0.68

D;D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.9

L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.4

N;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.25

T;T;T

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

0.99

D;D;.

Vest4

0.62

MutPred

0.44

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;

MVP

0.92

MPC

0.55

ClinPred

0.92

GERP RS

5.8

Varity_R

0.21

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over