NM_002033.4:c.361C>G

Variant names:

• chr11-94544494-C-G
• rs766133836
• NM_002033.4:c.361C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002033.4(FUT4):​c.361C>G​(p.Leu121Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000545 in 1,468,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. L121R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: FUT4 NM_002033.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.140
• Publications: 0 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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016063899).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUT4	NM_002033.4	c.361C>G	p.Leu121Val	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.361C>G	p.Leu121Val	missense_variant	Exon 1 of 1	6	NM_002033.4	ENSP00000351602.2
PIWIL4	ENST00000543336.5	n.-121+505C>G		intron_variant	Intron 1 of 13	2		ENSP00000444575.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151948 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000777

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000431 AC: 3 AN: 69574 AF XY: 0.0000748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000304 AC: 4 AN: 1316924 Hom.: 0 Cov.: 30 AF XY: 0.00000308 AC XY: 2 AN XY: 648406

African (AFR) AF: 0.00 AC: 0 AN: 26740

American (AMR) AF: 0.00 AC: 0 AN: 26782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22710

East Asian (EAS) AF: 0.000141 AC: 4 AN: 28274

South Asian (SAS) AF: 0.00 AC: 0 AN: 71716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3936

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1048890

Other (OTH) AF: 0.00 AC: 0 AN: 54674

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151948 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74224

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000777 AC: 4 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000273 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.361C>G (p.L121V) alteration is located in exon 1 (coding exon 1) of the FUT4 gene. This alteration results from a C to G substitution at nucleotide position 361, causing the leucine (L) at amino acid position 121 to be replaced by a valine (V). 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	0.065
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.3
DANN	Benign	0.92
DEOGEN2	Benign	0.079	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.14
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.012
Sift	Benign	0.35	T
Sift4G	Benign	0.12	T
Polyphen		0.0050	B
Vest4		0.017
MutPred		0.16		Loss of helix (P = 0.079);
MVP		0.29
MPC		0.79
ClinPred		0.035	T
GERP RS		-0.42
Varity_R		0.048
gMVP		0.099
Mutation Taster		=99/1	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: rs766133836; hg19: chr11-94277660;