15-49367608-A-G

Variant names:

• chr15-49367608-A-G
• rs1596613924
• NM_152647.3:c.1111T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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

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

Verdict is Uncertain_significance. Variant got 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	c.1111T>C	p.Ser371Pro	missense_variant, splice_region_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.1111T>C	p.Ser371Pro	missense_variant, splice_region_variant	Exon 13 of 16	2	NM_152647.3	ENSP00000299338.6
GALK2	ENST00000559580.5	c.*77A>G		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000453257.1
GALK2	ENST00000558399.5	c.*72A>G		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000453252.1
FAM227B	ENST00000559573.3	n.420+3694T>C		intron_variant	Intron 3 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397946 Hom.: 0 Cov.: 29 AF XY: 0.00000144 AC XY: 1 AN XY: 694264

Gnomad4 AFR exome AF: 0.0000690

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000867 AC: 3 AN: 3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.079	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.27
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.33		Gain of loop (P = 0.0166);
MVP		0.11
MPC		0.31
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.56
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs1596613924; hg19: chr15-49659805;