Variant 15-49328675-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152647.3(FAM227B):c.1420C>T(p.Arg474Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,554,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

FAM227B
NM_152647.3 missense, splice_region

Scores

Splicing: ADA: 0.2868

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.794

Variant links:

Genes affected

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

FAM227B links:

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]

GALK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.07262206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM227B	NM_152647.3 linkuse as main transcript	c.1420C>T	p.Arg474Cys	missense_variant, splice_region_variant	16/16	ENST00000299338.11
GALK2	NM_002044.4 linkuse as main transcript	c.*516G>A		3_prime_UTR_variant	10/10	ENST00000560031.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM227B	ENST00000299338.11 linkuse as main transcript	c.1420C>T	p.Arg474Cys	missense_variant, splice_region_variant	16/16	2	NM_152647.3	P1	Q96M60-1
GALK2	ENST00000560031.6 linkuse as main transcript	c.*516G>A		3_prime_UTR_variant	10/10	1	NM_002044.4	P1	Q01415-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000782

AC:

AN:

166170

Hom.:

AF XY:

0.0000574

AC XY:

AN XY:

87088

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000402

Gnomad ASJ exome

AF:

0.000577

Gnomad EAS exome

AF:

0.000585

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1402692

Hom.:

Cov.:

AF XY:

0.0000361

AC XY:

AN XY:

692392

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000278

Gnomad4 ASJ exome

AF:

0.000238

Gnomad4 EAS exome

AF:

0.000631

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000130

Gnomad4 OTH exome

AF:

0.0000516

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000761

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000291

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2022

The c.1420C>T (p.R474C) alteration is located in exon 16 (coding exon 15) of the FAM227B gene. This alteration results from a C to T substitution at nucleotide position 1420, causing the arginine (R) at amino acid position 474 to be replaced by a cysteine (C). 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

-0.38

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.71

M_CAP

Benign

0.010

MetaRNN

Benign

0.073

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.90

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.3

REVEL

Benign

0.036

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.23

Vest4

0.13

MVP

0.11

MPC

0.29

ClinPred

0.14

GERP RS

3.2

Varity_R

0.12

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.29

dbscSNV1_RF

Benign

0.33

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over