15-49367608-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_152647.3(FAM227B):c.1111T>C(p.Ser371Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000143 in 1,397,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FAM227B
NM_152647.3 missense, splice_region

Scores

Splicing: ADA: 0.8488

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.71

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM227B	NM_152647.3 link	c.1111T>C	p.Ser371Pro	missense_variant, splice_region_variant	Exon 13 of 16	ENST00000299338.11	NP_689860.2	Q96M60-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM227B	ENST00000299338.11 link	c.1111T>C	p.Ser371Pro	missense_variant, splice_region_variant	Exon 13 of 16	2	NM_152647.3	ENSP00000299338.6	Q96M60-1
GALK2	ENST00000559580.5 link	c.*77A>G		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000453257.1	H0YLL8
GALK2	ENST00000558399.5 link	c.*72A>G		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000453252.1	H0YLL3
FAM227B	ENST00000559573.3 link	n.420+3694T>C		intron_variant	Intron 3 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1397946

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694264

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000690

AC:

AN:

28988

American (AMR)

AF:

0.00

AC:

AN:

27004

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24140

East Asian (EAS)

AF:

0.00

AC:

AN:

35846

South Asian (SAS)

AF:

0.00

AC:

AN:

73074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092754

Other (OTH)

AF:

0.00

AC:

AN:

57696

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Asia WGS

AF:

0.000867

AC:

AN:

3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 07, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1111T>C (p.S371P) alteration is located in exon 13 (coding exon 12) of the FAM227B gene. This alteration results from a T to C substitution at nucleotide position 1111, causing the serine (S) at amino acid position 371 to be replaced by a proline (P). 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

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.42

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

-0.079

MutationAssessor

Uncertain

2.3

PhyloP100

5.7

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.27

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.75

MutPred

0.33

Gain of loop (P = 0.0166);

MVP

0.11

MPC

0.31

ClinPred

0.99

GERP RS

5.2

Varity_R

0.56

gMVP

0.41

Mutation Taster

=49/51

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.85

dbscSNV1_RF

Pathogenic

0.83

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

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15-49367608-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over