rs144550328

chr8-117822563-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000127.3(EXT1):c.1319G>A(p.Arg440His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,613,272 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R440C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: EXT1 NM_000127.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.87

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 8-117822563-C-T is Benign according to our data. Variant chr8-117822563-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 526298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT1	NM_000127.3	c.1319G>A	p.Arg440His	missense_variant	5/11	ENST00000378204.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT1	ENST00000378204.7	c.1319G>A	p.Arg440His	missense_variant	5/11	1	NM_000127.3	P1
EXT1	ENST00000684189.1	n.786G>A		non_coding_transcript_exon_variant	5/11
EXT1	ENST00000436216.2	c.*120G>A		3_prime_UTR_variant, NMD_transcript_variant	6/6	3
EXT1	ENST00000437196.1	c.*210G>A		3_prime_UTR_variant, NMD_transcript_variant	4/10	5

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 250738 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000517

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000207 AC: 303 AN: 1461020 Hom.: 0 Cov.: 31 AF XY: 0.000193 AC XY: 140 AN XY: 726854

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000396

Gnomad4 NFE exome AF: 0.000234

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74448

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000211 Hom.: 0

Bravo AF: 0.000117

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital exostosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

- -

EXT1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.56
Sift	Benign	0.34	T
Sift4G	Benign	0.28	T
Polyphen		0.24	B
Vest4		0.88
MVP		0.96
MPC		0.53
ClinPred		0.18	T
GERP RS		5.9
Varity_R		0.15
gMVP		0.90

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

Other links and lift over

dbSNP: rs144550328; hg19: chr8-118834802;