15-49335477-G-T

Variant names:

• chr15-49335477-G-T
• rs371011363
• NM_152647.3:c.1291C>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.1291C>A​(p.Arg431Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R431C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FAM227B NM_152647.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.389
• 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: 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=0.03210011).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM227B	NM_152647.3	c.1291C>A	p.Arg431Ser	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.1291C>A	p.Arg431Ser	missense_variant	Exon 14 of 16	2	NM_152647.3	ENSP00000299338.6
GALK2	ENST00000559580.5	c.448+7347G>T		intron_variant	Intron 3 of 3	5		ENSP00000453257.1
GALK2	ENST00000558399.5	c.425+15672G>T		intron_variant	Intron 3 of 3	5		ENSP00000453252.1
FAM227B	ENST00000559573.3	n.421-3628C>A		intron_variant	Intron 3 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460960 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726856

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111280

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.7
DANN	Benign	0.77
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.39
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.063
Sift	Benign	0.73	T
Sift4G	Benign	0.52	T
Polyphen		0.047	B
Vest4		0.19
MutPred		0.28		Loss of MoRF binding (P = 0.0342);
MVP		0.014
MPC		0.067
ClinPred		0.056	T
GERP RS		-3.1
Varity_R		0.082
gMVP		0.19

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: rs371011363; hg19: chr15-49627674;