15-49367574-C-T

Variant names:

• chr15-49367574-C-T
• rs139377249
• NM_152647.3:c.1145G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152647.3(FAM227B):​c.1145G>A​(p.Arg382His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,600,198 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: FAM227B NM_152647.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00900
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043037206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM227B	NM_152647.3	c.1145G>A	p.Arg382His	missense_variant	Exon 13 of 16	ENST00000299338.11	NP_689860.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM227B	ENST00000299338.11	c.1145G>A	p.Arg382His	missense_variant	Exon 13 of 16	2	NM_152647.3	ENSP00000299338.6
GALK2	ENST00000559580.5	c.*43C>T		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000453257.1
GALK2	ENST00000558399.5	c.*38C>T		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000453252.1
FAM227B	ENST00000559573.3	n.420+3728G>A		intron_variant	Intron 3 of 4	3

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 151940 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000802 AC: 19 AN: 236792 AF XY: 0.0000624

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000394 AC: 57 AN: 1448258 Hom.: 0 Cov.: 30 AF XY: 0.0000430 AC XY: 31 AN XY: 720222

African (AFR) AF: 0.00135 AC: 44 AN: 32498

American (AMR) AF: 0.00 AC: 0 AN: 40414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25722

East Asian (EAS) AF: 0.00 AC: 0 AN: 39250

South Asian (SAS) AF: 0.00 AC: 0 AN: 82606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000902 AC: 10 AN: 1108904

Other (OTH) AF: 0.0000501 AC: 3 AN: 59856

GnomAD4 genome AF: 0.000303 AC: 46 AN: 151940 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74202

African (AFR) AF: 0.00106 AC: 44 AN: 41358

American (AMR) AF: 0.0000655 AC: 1 AN: 15258

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: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000358 Hom.: 0

Bravo AF: 0.000408

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1145G>A (p.R382H) alteration is located in exon 13 (coding exon 12) of the FAM227B gene. This alteration results from a G to A substitution at nucleotide position 1145, causing the arginine (R) at amino acid position 382 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	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.0090
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.057
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.014	D
Polyphen		0.86	P
Vest4		0.22
MVP		0.014
MPC		0.048
ClinPred		0.034	T
GERP RS		1.2
Varity_R		0.054
gMVP		0.25
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs139377249; hg19: chr15-49659771; COSMIC: COSV106410977; COSMIC: COSV106410977;