15-49335423-T-C

Variant names:

• chr15-49335423-T-C
• NM_152647.3:c.1345A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152647.3(FAM227B):​c.1345A>G​(p.Arg449Gly) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM227B NM_152647.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.190301).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM227B	NM_152647.3	c.1345A>G	p.Arg449Gly	missense_variant	Exon 14 of 16	ENST00000299338.11	NP_689860.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM227B	ENST00000299338.11	c.1345A>G	p.Arg449Gly	missense_variant	Exon 14 of 16	2	NM_152647.3	ENSP00000299338.6
GALK2	ENST00000559580.5	c.448+7293T>C		intron_variant	Intron 3 of 3	5		ENSP00000453257.1
GALK2	ENST00000558399.5	c.425+15618T>C		intron_variant	Intron 3 of 3	5		ENSP00000453252.1
FAM227B	ENST00000559573.3	n.421-3574A>G		intron_variant	Intron 3 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1345A>G (p.R449G) alteration is located in exon 14 (coding exon 13) of the FAM227B gene. This alteration results from a A to G substitution at nucleotide position 1345, causing the arginine (R) at amino acid position 449 to be replaced by a glycine (G). 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	0.21
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.062
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.7
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.15
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.76	P
Vest4		0.42
MutPred		0.35		Loss of sheet (P = 0.0142);
MVP		0.19
MPC		0.11
ClinPred		0.71	D
GERP RS		3.8
Varity_R		0.12
gMVP		0.16

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

hg19: chr15-49627620;