rs145035679

Positions:

• chr19-5831623-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000150.4(FUT6):​c.945C>A​(p.Tyr315Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00981 in 1,613,814 control chromosomes in the GnomAD database, including 375 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0085 (24 hom., cov: 31)
  • Exomes 𝑓: 0.010 (351 hom.)
• Consequence: FUT6 NM_000150.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.74

Genes affected

FUT6 (HGNC:4017): (fucosyltransferase 6) The protein encoded by this gene is a Golgi stack membrane protein that is involved in the creation of sialyl-Lewis X, an E-selectin ligand. Mutations in this gene are a cause of fucosyltransferase-6 deficiency. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 19-5831623-G-T is Benign according to our data. Variant chr19-5831623-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225367.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chr19-5831623-G-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FUT6	NM_000150.4	c.945C>A	p.Tyr315Ter	stop_gained	3/3	ENST00000318336.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FUT6	ENST00000318336.10	c.945C>A	p.Tyr315Ter	stop_gained	3/3	2	NM_000150.4	P1

Frequencies

GnomAD3 genomes AF: 0.00848 AC: 1291 AN: 152196 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.0619

Gnomad SAS AF: 0.0533

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.0174 AC: 4370 AN: 251054 Hom.: 143 AF XY: 0.0196 AC XY: 2656 AN XY: 135784

Gnomad AFR exome AF: 0.00291

Gnomad AMR exome AF: 0.00541

Gnomad ASJ exome AF: 0.0248

Gnomad EAS exome AF: 0.0697

Gnomad SAS exome AF: 0.0594

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.00995 AC: 14546 AN: 1461500 Hom.: 351 Cov.: 31 AF XY: 0.0115 AC XY: 8355 AN XY: 727068

Gnomad4 AFR exome AF: 0.00224

Gnomad4 AMR exome AF: 0.00541

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.0488

Gnomad4 SAS exome AF: 0.0561

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.00501

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.00846 AC: 1289 AN: 152314 Hom.: 24 Cov.: 31 AF XY: 0.00904 AC XY: 673 AN XY: 74478

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.0620

Gnomad4 SAS AF: 0.0531

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00525

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.00757 Hom.: 2

Bravo AF: 0.00829

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.00675 AC: 58

ExAC AF: 0.0176 AC: 2133

EpiCase AF: 0.00758

EpiControl AF: 0.00729

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fucosyltransferase 6 deficiency Uncertain:1 Benign:1

Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Tyr315Ter variant in FUT6 has been identified in at least 1 Indonesian individual with fucosyltransferase deficiency (PMID: 8175676). In vitro functional studies provide some evidence that the p.Tyr315Ter variant may impact protein function (PMID: 8175676). However, this variant was found in cis with another pathogenic variant and did not segregate with disease in multiple families, suggesting that it may not cause fucosyltransferase deficiency (PMID: 8175676). This variant is classified as benign for fucosyltransferase deficiency because it has been identified in >65% of East Asian chromosomes by ExAC (http://gnomad.broadinstitute.org/). -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Benign	-0.0017
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;D;D;D;D
Vest4		0.71
GERP RS		3.1

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: rs145035679; hg19: chr19-5831634; COSMIC: COSV54607469; COSMIC: COSV54607469;