Variant 1-100874231-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001033025.3(EXTL2):c.704C>T(p.Ala235Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,612,786 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 1 hom. )

Consequence

EXTL2
NM_001033025.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.06

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034500957).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXTL2	NM_001033025.3 linkuse as main transcript	c.704C>T	p.Ala235Val	missense_variant	5/5	ENST00000370114.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
EXTL2	ENST00000370114.8 linkuse as main transcript	c.704C>T	p.Ala235Val	missense_variant	5/5	1	NM_001033025.3	P1
EXTL2	ENST00000370113.7 linkuse as main transcript	c.704C>T	p.Ala235Val	missense_variant	5/5	1		P1
EXTL2	ENST00000450240.2 linkuse as main transcript	c.728C>T	p.Ala243Val	missense_variant	6/6	4
EXTL2	ENST00000535414.5 linkuse as main transcript	c.*189C>T		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes

AF:

0.000290

AC:

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000656

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000476

AC:

119

AN:

249852

Hom.:

AF XY:

0.000511

AC XY:

AN XY:

135004

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000479

Gnomad OTH exome

AF:

0.000825

GnomAD4 exome

AF:

0.000403

AC:

589

AN:

1460702

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

291

AN XY:

726636

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00106

Gnomad4 ASJ exome

AF:

0.00184

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000408

Gnomad4 OTH exome

AF:

0.000481

GnomAD4 genome

AF:

0.000289

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000655

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000473

Hom.:

Bravo

AF:

0.000400

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000379

AC:

EpiCase

AF:

0.000546

EpiControl

AF:

0.000712

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

May 26, 2022

The c.704C>T (p.A235V) 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 704, causing the alanine (A) at amino acid position 235 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

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.32

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.40

T;T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.035

FATHMM_MKL

Benign

0.58

M_CAP

Benign

0.021

MetaRNN

Benign

0.035

T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.1

M;M;.

MutationTaster

Benign

0.92

N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.28

T;T;T

Sift4G

Benign

0.26

T;T;.

Polyphen

0.0020

B;B;.

Vest4

0.10

MVP

0.77

MPC

0.16

ClinPred

0.015

GERP RS

5.1

Varity_R

0.057

gMVP

0.32

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