Genetic Variant NM_002033.4:c.137C>G (chr11-94544270-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002033.4(FUT4):c.137C>G(p.Ala46Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,390,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A46V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

FUT4
NM_002033.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.169

Publications

0 publications found

Variant links:

Genes affected

FUT4 (HGNC:4015): (fucosyltransferase 4) The product of this gene transfers fucose to N-acetyllactosamine polysaccharides to generate fucosylated carbohydrate structures. It catalyzes the synthesis of the non-sialylated antigen, Lewis x (CD15). [provided by RefSeq, Jan 2009]

FUT4 links:

PIWIL4 (HGNC:18444): (piwi like RNA-mediated gene silencing 4) PIWIL4 belongs to the Argonaute family of proteins, which function in development and maintenance of germline stem cells (Sasaki et al., 2003 [PubMed 12906857]).[supplied by OMIM, Mar 2008]

PIWIL4 links:

ENSG00000304830 (HGNC:):

ENSG00000304830 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058787286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUT4	NM_002033.4 link	c.137C>G	p.Ala46Gly	missense_variant	Exon 1 of 1	ENST00000358752.4	NP_002024.1	P22083-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FUT4	ENST00000358752.4 link	c.137C>G	p.Ala46Gly	missense_variant	Exon 1 of 1	6	NM_002033.4	ENSP00000351602.2	P22083-1
PIWIL4	ENST00000543336.5 link	n.-121+281C>G		intron_variant	Intron 1 of 13	2		ENSP00000444575.1	Q7Z3Z4-3
ENSG00000304830	ENST00000806516.1 link	n.-126G>C		upstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.19e-7

AC:

AN:

1390310

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689412

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28316

American (AMR)

AF:

0.00

AC:

AN:

35908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23372

East Asian (EAS)

AF:

0.00

AC:

AN:

32486

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4184

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082144

Other (OTH)

AF:

0.00

AC:

AN:

56916

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.089

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.27

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.059

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.17

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.34

REVEL

Benign

0.013

Sift

Benign

0.33

Sift4G

Pathogenic

0.0

Polyphen

0.0010

Vest4

0.047

MutPred

0.23

Gain of relative solvent accessibility (P = 0.0082);

MVP

0.12

MPC

0.79

ClinPred

0.12

GERP RS

1.2

PromoterAI

-0.00080

Neutral

(source)

Varity_R

0.036

gMVP

0.032

Mutation Taster

=94/6

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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NM_002033.4:c.137C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over