Genetic Variant FUT2:p.Arg138Cys (chr19-48703368-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000511.6(FUT2):c.412C>T(p.Arg138Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00877 in 1,613,062 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as confers sensitivity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0066 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 71 hom. )

Consequence

FUT2
NM_000511.6 missense

Scores

Clinical Significance

confers sensitivity no assertion criteria provided O:1

Conservation

PhyloP100: 0.560

Publications

20 publications found

Variant links:

Genes affected

FUT2 (HGNC:4013): (fucosyltransferase 2 (H blood group)) This gene is one of two encoding the galactoside 2-L-fucosyltransferase enzyme. The encoded protein is important for the final step in the soluble ABO blood group antigen synthesis pathway. It is also involved in cell-cell interaction, cell surface expression, and cell proliferation. Mutations in this gene are a cause of the H-Bombay blood group where red blood cells lack the H antigen. [provided by RefSeq, May 2022]

FUT2 links:

LOC105447645 (HGNC:):

LOC105447645 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014655948).

BS2

High Homozygotes in GnomAd4 at 6 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUT2	NM_000511.6 link	c.412C>T	p.Arg138Cys	missense_variant	Exon 2 of 2	ENST00000425340.3	NP_000502.4	Q10981A8K2L2
FUT2	NM_001097638.3 link	c.412C>T	p.Arg138Cys	missense_variant	Exon 2 of 2		NP_001091107.1	Q10981A8K2L2
LOC105447645	NR_131188.1 link	n.481G>A		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUT2	ENST00000425340.3 link	c.412C>T	p.Arg138Cys	missense_variant	Exon 2 of 2	1	NM_000511.6	ENSP00000387498.2		Q10981
FUT2	ENST00000522966.2 link	c.412C>T	p.Arg138Cys	missense_variant	Exon 2 of 2	2		ENSP00000430227.2		Q10981

Frequencies

GnomAD3 genomes

AF:

0.00661

AC:

1005

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00734

Gnomad ASJ

AF:

0.00951

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000631

Gnomad FIN

AF:

0.00584

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00619

AC:

1549

AN:

250440

AF XY:

0.00625

show subpopulations

Gnomad AFR exome

AF:

0.00143

Gnomad AMR exome

AF:

0.00492

Gnomad ASJ exome

AF:

0.00725

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00536

Gnomad NFE exome

AF:

0.00984

Gnomad OTH exome

AF:

0.00620

GnomAD4 exome

AF:

0.00899

AC:

13138

AN:

1460876

Hom.:

Cov.:

AF XY:

0.00862

AC XY:

6264

AN XY:

726698

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

33480

American (AMR)

AF:

0.00517

AC:

231

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00719

AC:

188

AN:

26130

East Asian (EAS)

AF:

0.000101

AC:

AN:

39698

South Asian (SAS)

AF:

0.000664

AC:

AN:

85888

European-Finnish (FIN)

AF:

0.00578

AC:

306

AN:

52908

Middle Eastern (MID)

AF:

0.00468

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0107

AC:

11856

AN:

1111944

Other (OTH)

AF:

0.00701

AC:

423

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

837

1673

2510

3346

4183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00660

AC:

1004

AN:

152186

Hom.:

Cov.:

AF XY:

0.00618

AC XY:

460

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

41568

American (AMR)

AF:

0.00733

AC:

112

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00951

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000632

AC:

AN:

4750

European-Finnish (FIN)

AF:

0.00584

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0102

AC:

692

AN:

68018

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

115

173

230

288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00914

Hom.:

Bravo

AF:

0.00644

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0104

AC:

ExAC

AF:

0.00617

AC:

748

EpiCase

AF:

0.0101

EpiControl

AF:

0.0110

ClinVar

Significance: confers sensitivity

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Familial Otitis Media

Other:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance:confers sensitivity

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.13

.;T;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.84

.;.;T

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.0

.;M;M

PhyloP100

0.56

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.0050

D;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.59, 0.85

MVP

0.96

MPC

0.85

ClinPred

0.033

GERP RS

4.8

Varity_R

0.44

gMVP

0.49

Mutation Taster

=85/15

polymorphism

(source)

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

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chr19-48703368-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over