8-28717383-G-C

Variant names:

• chr8-28717383-G-C
• rs116659770
• NM_001440.4:c.1324G>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:4
• Conservation: PhyloP100: 1.62
• Publications: 4 publications found

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]

EXTL3 Gene-Disease associations (from GenCC):

• immunoskeletal dysplasia with neurodevelopmental abnormalities

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXTL3	NM_001440.4	MANE Select	c.1324G>C	p.Val442Leu	missense	Exon 3 of 7	NP_001431.1
	EXTL3	NM_001437797.1		c.1324G>C	p.Val442Leu	missense	Exon 2 of 6	NP_001424726.1
	EXTL3	NM_001438399.1		c.1324G>C	p.Val442Leu	missense	Exon 3 of 7	NP_001425328.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXTL3	ENST00000220562.9	TSL:1 MANE Select	c.1324G>C	p.Val442Leu	missense	Exon 3 of 7	ENSP00000220562.4
	EXTL3	ENST00000696177.1		c.1324G>C	p.Val442Leu	missense	Exon 2 of 6	ENSP00000512467.1
	EXTL3	ENST00000696178.1		c.1324G>C	p.Val442Leu	missense	Exon 3 of 7	ENSP00000512468.1

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

GnomAD2 exomes AF: 0.00336 AC: 844 AN: 251448 AF XY: 0.00230

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 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

African (AFR) AF: 0.0460 AC: 1541 AN: 33478

American (AMR) AF: 0.00237 AC: 106 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00371 AC: 97 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.000123 AC: 137 AN: 1112012

Other (OTH) AF: 0.00296 AC: 179 AN: 60396

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

African (AFR) AF: 0.0424 AC: 1761 AN: 41554

American (AMR) AF: 0.00556 AC: 85 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68028

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 27, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Immunoskeletal dysplasia with neurodevelopmental abnormalities Benign:1

May 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.74	N
PhyloP100		1.6
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.25
Sift	Benign	0.51	T
Sift4G	Benign	0.73	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
Mutation Taster		=92/8	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: rs116659770; hg19: chr8-28574900;