Genetic Variant NM_000127.3:c.*142_*144delAAA (chr8-117799567-CTTT-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000127.3(EXT1):c.*142_*144delAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 642,806 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EXT1
NM_000127.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.68

Publications

0 publications found

Variant links:

Genes affected

EXT1 (HGNC:3512): (exostosin glycosyltransferase 1) This gene encodes an endoplasmic reticulum-resident type II transmembrane glycosyltransferase involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type I form of multiple exostoses. [provided by RefSeq, Jul 2008]

EXT1 Gene-Disease associations (from GenCC):

exostoses, multiple, type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
chondrosarcoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
hereditary multiple osteochondromas
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EXT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT1	NM_000127.3 link	c.142_144delAAA		3_prime_UTR_variant	Exon 11 of 11	ENST00000378204.7	NP_000118.2	Q16394

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
EXT1	ENST00000378204.7 link	c.142_144delAAA	3_prime_UTR_variant	Exon 11 of 11	1	NM_000127.3	ENSP00000367446.3	Q16394
EXT1	ENST00000684189.1 link	n.1850_1852delAAA	non_coding_transcript_exon_variant	Exon 11 of 11
EXT1	ENST00000437196.1 link	n.1274_1276delAAA	downstream_gene_variant		5		ENSP00000407299.1	F8WF54
EXT1	ENST00000684443.1 link	n.17_19delAAA	downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

146280

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

642806

Hom.:

AF XY:

0.0000120

AC XY:

AN XY:

332968

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:

15312

American (AMR)

AF:

0.00

AC:

AN:

23934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15506

East Asian (EAS)

AF:

0.00

AC:

AN:

27802

South Asian (SAS)

AF:

0.0000200

AC:

AN:

49892

European-Finnish (FIN)

AF:

0.0000288

AC:

AN:

34726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3050

European-Non Finnish (NFE)

AF:

0.00000906

AC:

AN:

441596

Other (OTH)

AF:

0.0000323

AC:

AN:

30988

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.232

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

146280

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71080

African (AFR)

AF:

0.00

AC:

AN:

39604

American (AMR)

AF:

0.00

AC:

AN:

14682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3378

East Asian (EAS)

AF:

0.00

AC:

AN:

5044

South Asian (SAS)

AF:

0.00

AC:

AN:

4578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66392

Other (OTH)

AF:

0.00

AC:

AN:

2032

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

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

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NM_000127.3:c.142_144delAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over