Genetic Variant NM_001033025.3:c.265G>A (chr1-100877644-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_001033025.3(EXTL2):c.265G>A(p.Val89Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EXTL2
NM_001033025.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.256

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08597657).

BP6

Variant 1-100877644-C-T is Benign according to our data. Variant chr1-100877644-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3091295.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033025.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXTL2	NM_001033025.3	MANE Select	c.265G>A	p.Val89Ile	missense	Exon 3 of 5	NP_001028197.1	Q9UBQ6
EXTL2	NM_001261441.2		c.289G>A	p.Val97Ile	missense	Exon 4 of 6	NP_001248370.1
EXTL2	NM_001439.4		c.265G>A	p.Val89Ile	missense	Exon 3 of 5	NP_001430.1	Q9UBQ6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXTL2	ENST00000370114.8	TSL:1 MANE Select	c.265G>A	p.Val89Ile	missense	Exon 3 of 5	ENSP00000359132.3	Q9UBQ6
EXTL2	ENST00000370113.7	TSL:1	c.265G>A	p.Val89Ile	missense	Exon 3 of 5	ENSP00000359131.3	Q9UBQ6
EXTL2	ENST00000886545.1		c.289G>A	p.Val97Ile	missense	Exon 4 of 6	ENSP00000556603.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461384

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727006

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111688

Other (OTH)

AF:

0.00

AC:

AN:

60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.7

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.19

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.84

M_CAP

Benign

0.011

MetaRNN

Benign

0.086

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.62

PhyloP100

0.26

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.51

REVEL

Benign

0.11

Sift

Benign

0.18

Sift4G

Benign

0.37

Polyphen

0.0010

Vest4

0.080

MutPred

0.51

Gain of ubiquitination at K94 (P = 0.1245)

MVP

0.18

MPC

0.13

ClinPred

0.084

GERP RS

0.13

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.029

gMVP

0.16

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over