rs116659770

chr8-28717383-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001440.4(EXTL3):c.1324G>C(p.Val442Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,614,190 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (42 hom.)
• Consequence: EXTL3 NM_001440.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.62

Genes affected

EXTL3 (HGNC:3518): (exostosin like glycosyltransferase 3) This gene encodes a single-pass membrane protein which functions as a glycosyltransferase. The encoded protein catalyzes the transfer of N-acetylglucosamine to glycosaminoglycan chains. This reaction is important in heparin and heparan sulfate synthesis. Alternative splicing results in the multiple transcript variants. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037114024).
• BP6: Variant 8-28717383-G-C is Benign according to our data. Variant chr8-28717383-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 446049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0124 (1889/152302) while in subpopulation AFR AF= 0.0424 (1761/41554). AF 95% confidence interval is 0.0407. There are 43 homozygotes in gnomad4. There are 868 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXTL3	NM_001440.4	c.1324G>C	p.Val442Leu	missense_variant	3/7	ENST00000220562.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXTL3	ENST00000220562.9	c.1324G>C	p.Val442Leu	missense_variant	3/7	1	NM_001440.4	P1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1887 AN: 152184 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00336 AC: 844 AN: 251448 Hom.: 16 AF XY: 0.00230 AC XY: 312 AN XY: 135904

Gnomad AFR exome AF: 0.0434

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00142 AC: 2073 AN: 1461888 Hom.: 42 Cov.: 33 AF XY: 0.00121 AC XY: 881 AN XY: 727246

Gnomad4 AFR exome AF: 0.0460

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00371

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.0124 AC: 1889 AN: 152302 Hom.: 43 Cov.: 32 AF XY: 0.0117 AC XY: 868 AN XY: 74472

Gnomad4 AFR AF: 0.0424

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00229 Hom.: 6

Bravo AF: 0.0143

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0411 AC: 181

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00404 AC: 491

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 27, 2017	- -

Immunoskeletal dysplasia with neurodevelopmental abnormalities Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	7.0
Dann	Benign	0.67
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.25
Sift	Benign	0.51	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.0040	.;B
Vest4		0.14
MVP		0.69
MPC		0.31
ClinPred		0.0036	T
GERP RS		-0.76
Varity_R		0.042
gMVP		0.64

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: rs116659770; hg19: chr8-28574900;