8-117799567-CTTTTT-CTTTTTT

Variant names:

• chr8-117799567-C-CT
• rs71739430
• NM_000127.3:c.*144dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000127.3(EXT1):​c.*144dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 770,106 control chromosomes in the GnomAD database, including 4 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0043 (4 hom., cov: 26)
  • Exomes 𝑓: 0.013 (0 hom.)
• Consequence: EXT1 NM_000127.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.68
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00427 (625/146298) while in subpopulation AFR AF = 0.0132 (525/39684). AF 95% confidence interval is 0.0123. There are 4 homozygotes in GnomAd4. There are 332 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 625 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT1	NM_000127.3	c.*144dupA		3_prime_UTR_variant	Exon 11 of 11	ENST00000378204.7	NP_000118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXT1	ENST00000378204.7	c.*144dupA		3_prime_UTR_variant	Exon 11 of 11	1	NM_000127.3	ENSP00000367446.3
EXT1	ENST00000684189.1	n.1852dupA		non_coding_transcript_exon_variant	Exon 11 of 11
EXT1	ENST00000684443.1	n.*19dupA		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00425 AC: 621 AN: 146244 Hom.: 4 Cov.: 26

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.00397

Gnomad SAS AF: 0.000874

Gnomad FIN AF: 0.000214

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000542

Gnomad OTH AF: 0.00344

GnomAD4 exome AF: 0.0133 AC: 8297 AN: 623808 Hom.: 0 Cov.: 0 AF XY: 0.0131 AC XY: 4227 AN XY: 323070

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

African (AFR) AF: 0.0319 AC: 466 AN: 14630

American (AMR) AF: 0.00954 AC: 222 AN: 23266

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 189 AN: 14962

East Asian (EAS) AF: 0.0178 AC: 464 AN: 26090

South Asian (SAS) AF: 0.0101 AC: 486 AN: 47950

European-Finnish (FIN) AF: 0.0133 AC: 446 AN: 33614

Middle Eastern (MID) AF: 0.0101 AC: 30 AN: 2972

European-Non Finnish (NFE) AF: 0.0129 AC: 5552 AN: 430396

Other (OTH) AF: 0.0148 AC: 442 AN: 29928

⚠️ 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.

GnomAD4 genome AF: 0.00427 AC: 625 AN: 146298 Hom.: 4 Cov.: 26 AF XY: 0.00467 AC XY: 332 AN XY: 71128

African (AFR) AF: 0.0132 AC: 525 AN: 39684

American (AMR) AF: 0.00184 AC: 27 AN: 14696

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 4 AN: 3378

East Asian (EAS) AF: 0.00398 AC: 20 AN: 5028

South Asian (SAS) AF: 0.000876 AC: 4 AN: 4566

European-Finnish (FIN) AF: 0.000214 AC: 2 AN: 9356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000542 AC: 36 AN: 66360

Other (OTH) AF: 0.00342 AC: 7 AN: 2048

Alfa AF: 0.000247 Hom.: 64

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs71739430; hg19: chr8-118811806;