15-49331794-A-T

Variant names:

• chr15-49331794-A-T
• NM_152647.3:c.1405T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152647.3(FAM227B):​c.1405T>A​(p.Phe469Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM227B NM_152647.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

Genes affected

FAM227B (HGNC:26543): (family with sequence similarity 227 member B)

GALK2 (HGNC:4119): (galactokinase 2) This gene encodes a highly efficient N-acetylgalactosamine (GalNAc) kinase, which has galactokinase activity when galactose is present at high concentrations. The encoded protein is a member of the GHMP kinase family. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25490212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM227B	NM_152647.3	c.1405T>A	p.Phe469Ile	missense_variant	Exon 15 of 16	ENST00000299338.11	NP_689860.2
GALK2	NM_002044.4	c.*3635A>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000560031.6	NP_002035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM227B	ENST00000299338.11	c.1405T>A	p.Phe469Ile	missense_variant	Exon 15 of 16	2	NM_152647.3	ENSP00000299338.6
GALK2	ENST00000560031.6	c.*3635A>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_002044.4	ENSP00000453129.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1405T>A (p.F469I) alteration is located in exon 15 (coding exon 14) of the FAM227B gene. This alteration results from a T to A substitution at nucleotide position 1405, causing the phenylalanine (F) at amino acid position 469 to be replaced by an isoleucine (I). 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	0.32
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.045	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.90	L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.095
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.35		Gain of ubiquitination at K468 (P = 0.0737);
MVP		0.076
MPC		0.32
ClinPred		0.75	D
GERP RS		4.5
Varity_R		0.35
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-49623991;