15-49541757-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152647.3(FAM227B):c.797C>T(p.Ala266Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000288 in 1,389,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: FAM227B NM_152647.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

Genes affected

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

LOC105370811 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM227B	NM_152647.3	c.797C>T	p.Ala266Val	missense_variant	10/16	ENST00000299338.11
LOC105370811	XR_001751537.2	n.88+3296G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM227B	ENST00000299338.11	c.797C>T	p.Ala266Val	missense_variant	10/16	2	NM_152647.3	P1
FAM227B	ENST00000561064.5	c.695C>T	p.Ala232Val	missense_variant	9/11	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000288 AC: 4 AN: 1389080 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 688976

Gnomad4 AFR exome AF: 0.00

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: 0.00000372

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.797C>T (p.A266V) alteration is located in exon 10 (coding exon 9) of the FAM227B gene. This alteration results from a C to T substitution at nucleotide position 797, causing the alanine (A) at amino acid position 266 to be replaced by a valine (V). 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	0.58
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0099	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.50	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.011	D;D
Sift4G	Benign	0.070	T;T
Polyphen		0.99	D;D
Vest4		0.48
MutPred		0.39		Loss of disorder (P = 0.1048);.;
MVP		0.16
MPC		0.28
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.31
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2071095489; hg19: chr15-49833954;