chr19-5831661-G-C

Position:

• chr19-5831661-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000150.4(FUT6):​c.907C>G​(p.Arg303Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0984 in 1,612,286 control chromosomes in the GnomAD database, including 13,495 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R303L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1547 hom., cov: 31)
  • Exomes 𝑓: 0.097 (11948 hom.)
• Consequence: FUT6 NM_000150.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.281

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001342386).
• BP6: Variant 19-5831661-G-C is Benign according to our data. Variant chr19-5831661-G-C is described in ClinVar as [Benign]. Clinvar id is 979160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FUT6	NM_000150.4	c.907C>G	p.Arg303Gly	missense_variant	3/3	ENST00000318336.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FUT6	ENST00000318336.10	c.907C>G	p.Arg303Gly	missense_variant	3/3	2	NM_000150.4	P1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16677 AN: 151970 Hom.: 1536 Cov.: 31

Gnomad AFR AF: 0.0671

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.0914

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0736

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.154 AC: 38261 AN: 249180 Hom.: 5292 AF XY: 0.140 AC XY: 18898 AN XY: 135062

Gnomad AFR exome AF: 0.0678

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.0973

Gnomad EAS exome AF: 0.458

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.0731

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.0972 AC: 141902 AN: 1460200 Hom.: 11948 Cov.: 32 AF XY: 0.0957 AC XY: 69546 AN XY: 726418

Gnomad4 AFR exome AF: 0.0637

Gnomad4 AMR exome AF: 0.357

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.471

Gnomad4 SAS exome AF: 0.0988

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.0723

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.110 AC: 16704 AN: 152086 Hom.: 1547 Cov.: 31 AF XY: 0.118 AC XY: 8758 AN XY: 74352

Gnomad4 AFR AF: 0.0670

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.0914

Gnomad4 EAS AF: 0.452

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.139

Gnomad4 NFE AF: 0.0736

Gnomad4 OTH AF: 0.125

Alfa AF: 0.0503 Hom.: 63

Bravo AF: 0.123

ExAC AF: 0.140 AC: 17032

EpiCase AF: 0.0715

EpiControl AF: 0.0728

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fucosyltransferase 6 deficiency Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous p.Arg303Gly variant in FUT6 has been identified in 9 Indonesian and 2 Swedish individuals without fucosyltransferase deficiency (PMID: 11102976). In vitro functional studies provide some evidence that the p.Arg303Gly variant may not impact protein function (PMID: 11102976). However, these types of assays may not accurately represent biological function. This variant is classified as benign for fucosyltransferase deficiency because it has been identified in >40% of East Asian chromosomes by ExAC (http://gnomad.broadinstitute.org/). -

FUT6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as 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	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.017	T;T;T;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.084	N
MetaRNN	Benign	0.0013	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L;L;L;L;L
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.1	N;N;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.084	T;T;T;T;.
Sift4G	Benign	0.39	T;T;T;T;T
Polyphen		0.049	B;B;B;B;.
Vest4		0.13
MPC		0.88
ClinPred		0.013	T
GERP RS		3.0
Varity_R		0.18
gMVP		0.21

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: rs61147939; hg19: chr19-5831672; COSMIC: COSV54604636; COSMIC: COSV54604636;