chr15-49328674-C-T

Variant names:

• chr15-49328674-C-T
• rs774318678
• NM_152647.3:c.1421G>A

Variant summary

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

The NM_152647.3(FAM227B):​c.1421G>A​(p.Arg474His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,555,252 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R474C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (1 hom.)
• Consequence: FAM227B NM_152647.3 missense, splice_region
• Scores: Splicing: ADA: 0.0006167
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0740
• Publications: 1 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: 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=0.020189673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM227B	NM_152647.3	c.1421G>A	p.Arg474His	missense_variant, splice_region_variant	Exon 16 of 16	ENST00000299338.11	NP_689860.2
GALK2	NM_002044.4	c.*515C>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.1421G>A	p.Arg474His	missense_variant, splice_region_variant	Exon 16 of 16	2	NM_152647.3	ENSP00000299338.6
GALK2	ENST00000560031.6	c.*515C>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_002044.4	ENSP00000453129.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151952 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000897 AC: 15 AN: 167162 AF XY: 0.0000685

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000800

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000831

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000304

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000534 AC: 75 AN: 1403300 Hom.: 1 Cov.: 32 AF XY: 0.0000592 AC XY: 41 AN XY: 692772

African (AFR) AF: 0.00 AC: 0 AN: 31984

American (AMR) AF: 0.0000556 AC: 2 AN: 35952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25200

East Asian (EAS) AF: 0.000137 AC: 5 AN: 36504

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.0000537 AC: 58 AN: 1080054

Other (OTH) AF: 0.000155 AC: 9 AN: 58116

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151952 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74196

African (AFR) AF: 0.00 AC: 0 AN: 41342

American (AMR) AF: 0.00 AC: 0 AN: 15256

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68010

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

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000481 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1421G>A (p.R474H) alteration is located in exon 16 (coding exon 15) of the FAM227B gene. This alteration results from a G to A substitution at nucleotide position 1421, causing the arginine (R) at amino acid position 474 to be replaced by a histidine (H). 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	0.092
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.074
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.033
Sift	Benign	0.11	T
Sift4G	Benign	0.11	T
Polyphen		0.054	B
Vest4		0.045
MutPred		0.21		Loss of MoRF binding (P = 0.0626);
MVP		0.014
MPC		0.047
ClinPred		0.030	T
GERP RS		-1.1
Varity_R		0.033
gMVP		0.40
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00062
dbscSNV1_RF	Benign	0.010
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: rs774318678; hg19: chr15-49620871;