chr15-49328675-G-A

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

3
16
Splicing: ADA: 0.2868
2

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)
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]

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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
FAM227BNM_152647.3 linkuse as main transcriptc.1420C>T p.Arg474Cys missense_variant, splice_region_variant 16/16 ENST00000299338.11
GALK2NM_002044.4 linkuse as main transcriptc.*516G>A 3_prime_UTR_variant 10/10 ENST00000560031.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FAM227BENST00000299338.11 linkuse as main transcriptc.1420C>T p.Arg474Cys missense_variant, splice_region_variant 16/162 NM_152647.3 P1Q96M60-1
GALK2ENST00000560031.6 linkuse as main transcriptc.*516G>A 3_prime_UTR_variant 10/101 NM_002044.4 P1Q01415-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152056
Hom.:
0
Cov.:
32
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:
13
AN:
166170
Hom.:
0
AF XY:
0.0000574
AC XY:
5
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:
47
AN:
1402692
Hom.:
0
Cov.:
32
AF XY:
0.0000361
AC XY:
25
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:
2
AN:
152056
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
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.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000291
AC:
3
Asia WGS
AF:
0.000578
AC:
2
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 submitterclinical testingAmbry GeneticsJun 10, 2022The 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
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.18
T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.32
FATHMM_MKL
Benign
0.48
N
LIST_S2
Benign
0.71
T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.073
T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
0.90
L
MutationTaster
Benign
0.99
D;D
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-2.3
N
REVEL
Benign
0.036
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
0.23
B
Vest4
0.13
MVP
0.11
MPC
0.29
ClinPred
0.14
T
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.

Other links and lift over

dbSNP: rs776016532; hg19: chr15-49620872; API