19-5843999-A-C

Variant names:

• chr19-5843999-A-C
• ENST00000303225.12:c.841T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000149.4(FUT3):​c.841T>G​(p.Tyr281Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FUT3 NM_000149.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04

Genes affected

FUT3 (HGNC:4014): (fucosyltransferase 3 (Lewis blood group)) The Lewis histo-blood group system comprises a set of fucosylated glycosphingolipids that are synthesized by exocrine epithelial cells and circulate in body fluids. The glycosphingolipids function in embryogenesis, tissue differentiation, tumor metastasis, inflammation, and bacterial adhesion. They are secondarily absorbed to red blood cells giving rise to their Lewis phenotype. This gene is a member of the fucosyltransferase family, which catalyzes the addition of fucose to precursor polysaccharides in the last step of Lewis antigen biosynthesis. It encodes an enzyme with alpha(1,3)-fucosyltransferase and alpha(1,4)-fucosyltransferase activities. Mutations in this gene are responsible for the majority of Lewis antigen-negative phenotypes. Differences in the expression of this gene are associated with host susceptibility to viral infection. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUT3	NM_000149.4	c.841T>G	p.Tyr281Asp	missense_variant	Exon 3 of 3		NP_000140.1
FUT3	NM_001097639.3	c.841T>G	p.Tyr281Asp	missense_variant	Exon 3 of 3		NP_001091108.3
FUT3	NM_001097640.3	c.841T>G	p.Tyr281Asp	missense_variant	Exon 3 of 3		NP_001091109.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUT3	ENST00000303225.12	c.841T>G	p.Tyr281Asp	missense_variant	Exon 3 of 3	1		ENSP00000305603.5
FUT3	ENST00000458379.7	c.841T>G	p.Tyr281Asp	missense_variant	Exon 2 of 2	1		ENSP00000416443.1
FUT3	ENST00000589620.6	c.841T>G	p.Tyr281Asp	missense_variant	Exon 3 of 3	1		ENSP00000465804.1
FUT3	ENST00000589918.5	c.841T>G	p.Tyr281Asp	missense_variant	Exon 3 of 3	1		ENSP00000468123.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.841T>G (p.Y281D) alteration is located in exon 3 (coding exon 1) of the FUT3 gene. This alteration results from a T to G substitution at nucleotide position 841, causing the tyrosine (Y) at amino acid position 281 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Benign	0.15
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Benign	-0.52	T
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-9.1	D;D;.;.
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Vest4		0.57
MutPred		0.84		Gain of disorder (P = 0.0155);Gain of disorder (P = 0.0155);Gain of disorder (P = 0.0155);Gain of disorder (P = 0.0155);
MVP		0.50
MPC		2.0
ClinPred		1.0	D
GERP RS		2.3
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-5844010;