rs188859975

chr8-117819755-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000127.3(EXT1):c.1457C>T(p.Ala486Val) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,613,412 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A486A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: EXT1 NM_000127.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2 O:1
• Conservation: PhyloP100: 5.21

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019926697).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000118 (18/152284) while in subpopulation EAS AF= 0.0029 (15/5176). AF 95% confidence interval is 0.00179. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT1	NM_000127.3	c.1457C>T	p.Ala486Val	missense_variant	6/11	ENST00000378204.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT1	ENST00000378204.7	c.1457C>T	p.Ala486Val	missense_variant	6/11	1	NM_000127.3	P1
EXT1	ENST00000684189.1	n.924C>T		non_coding_transcript_exon_variant	6/11
EXT1	ENST00000437196.1	c.*348C>T		3_prime_UTR_variant, NMD_transcript_variant	5/10	5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000247 AC: 62 AN: 251190 Hom.: 0 AF XY: 0.000236 AC XY: 32 AN XY: 135748

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00299

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000107 AC: 156 AN: 1461128 Hom.: 1 Cov.: 31 AF XY: 0.000111 AC XY: 81 AN XY: 726852

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00353

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74470

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

-

- -

Multiple congenital exostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

EXT1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 01, 2019

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). -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	23
Dann	Benign	0.45
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.073
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.59	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.050	N
REVEL	Uncertain	0.38
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.014	B
Vest4		0.69
MVP		0.85
MPC		0.41
ClinPred		0.031	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.17
gMVP		0.75

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: rs188859975; hg19: chr8-118831994; COSMIC: COSV65479378;