NM_002033.4:c.40G>T

Variant names:

• chr11-94544173-G-T
• rs1196041469
• NM_002033.4:c.40G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002033.4(FUT4):​c.40G>T​(p.Ala14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,393,458 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A14G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: FUT4 NM_002033.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.794
• Publications: 2 publications found

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]

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]

ENSG00000304830 (HGNC:):

ACMG classification

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=0.0430924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUT4	NM_002033.4	c.40G>T	p.Ala14Ser	missense_variant	Exon 1 of 1	ENST00000358752.4	NP_002024.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUT4	ENST00000358752.4	c.40G>T	p.Ala14Ser	missense_variant	Exon 1 of 1	6	NM_002033.4	ENSP00000351602.2
PIWIL4	ENST00000543336.5	n.-121+184G>T		intron_variant	Intron 1 of 13	2		ENSP00000444575.1
ENSG00000304830	ENST00000806516.1	n.-29C>A		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000161 AC: 2 AN: 1241290 Hom.: 0 Cov.: 30 AF XY: 0.00000332 AC XY: 2 AN XY: 602504

African (AFR) AF: 0.00 AC: 0 AN: 23886

American (AMR) AF: 0.00 AC: 0 AN: 11288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17116

East Asian (EAS) AF: 0.00 AC: 0 AN: 27762

South Asian (SAS) AF: 0.00 AC: 0 AN: 55636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3426

European-Non Finnish (NFE) AF: 0.00000198 AC: 2 AN: 1007816

Other (OTH) AF: 0.00 AC: 0 AN: 50668

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.40G>T (p.A14S) alteration is located in exon 1 (coding exon 1) of the FUT4 gene. This alteration results from a G to T substitution at nucleotide position 40, causing the alanine (A) at amino acid position 14 to be replaced by a serine (S). 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	Benign	0.080
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.79
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.016
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0030	B
Vest4		0.047
MutPred		0.087		Gain of glycosylation at A14 (P = 0.0017);
MVP		0.22
MPC		0.73
ClinPred		0.21	T
GERP RS		-5.5
PromoterAI		-0.064	Neutral
Varity_R		0.057
gMVP		0.026
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1196041469; hg19: chr11-94277339;