19-48751005-T-C

Variant summary

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

The NM_001384359.1(FUT1):c.277A>G(p.Met93Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,438,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FUT1 NM_001384359.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

Genes affected

FUT1 (HGNC:4012): (fucosyltransferase 1 (H blood group)) This gene encodes a Golgi stack membrane protein that is involved in the creation of a precursor of the H antigen, which is required for the final step in the synthesis of soluble A and B antigens. This is one of two genes encoding the galactoside 2-L-fucosyltransferase enzyme. Mutations in this gene are a cause of the H-Bombay blood group. [provided by RefSeq, Aug 2016]

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, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FUT1	NM_001384359.1	c.277A>G	p.Met93Val	missense_variant	2/2	ENST00000645652.2
FUT1	NM_000148.4	c.277A>G	p.Met93Val	missense_variant	4/4
FUT1	NM_001329877.1	c.277A>G	p.Met93Val	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FUT1	ENST00000645652.2	c.277A>G	p.Met93Val	missense_variant	2/2		NM_001384359.1	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000429 AC: 1 AN: 233056 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125072

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1438892 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 712604

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bombay phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.75	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	0.60	N
PrimateAI	Benign	0.42	T
Polyphen		0.99	D;D
Vest4		0.65
MutPred		0.86		Loss of catalytic residue at M93 (P = 0.1016);Loss of catalytic residue at M93 (P = 0.1016);
MVP		0.97
MPC		0.97
ClinPred		0.98	D
GERP RS		2.6
Varity_R		0.88
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

LitVar

Other links and lift over

dbSNP: rs753159303; hg19: chr19-49254262;