Genetic Variant FAM227A:p.Val432Leu (chr22-38599849-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001013647.2(FAM227A):c.1294G>C(p.Val432Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000941 in 1,551,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

FAM227A
NM_001013647.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.182

Variant links:

Genes affected

FAM227A (HGNC:44197): (family with sequence similarity 227 member A)

FAM227A 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=0.10868326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM227A	NM_001013647.2 link	c.1294G>C	p.Val432Leu	missense_variant	Exon 14 of 17	ENST00000535113.7	NP_001013669.1	F5H4B4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM227A	ENST00000535113.7 link	c.1294G>C	p.Val432Leu	missense_variant	Exon 14 of 17	5	NM_001013647.2	ENSP00000445093.1	F5H4B4-1
FAM227A	ENST00000355830.11 link	c.1294G>C	p.Val432Leu	missense_variant	Exon 14 of 19	5		ENSP00000348086.7	A0A0A0MRD0
FAM227A	ENST00000540952.6 link	c.1294G>C	p.Val432Leu	missense_variant	Exon 14 of 17	5		ENSP00000493504.1	A0A2R8YCE3

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000832

AC:

AN:

156316

Hom.:

AF XY:

0.0000604

AC XY:

AN XY:

82838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000812

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.0000958

AC:

134

AN:

1399308

Hom.:

Cov.:

AF XY:

0.0000753

AC XY:

AN XY:

690164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000841

Gnomad4 ASJ exome

AF:

0.000159

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.0000831

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1294G>C (p.V432L) alteration is located in exon 14 (coding exon 13) of the FAM227A gene. This alteration results from a G to C substitution at nucleotide position 1294, causing the valine (V) at amino acid position 432 to be replaced by a leucine (L). 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

0.24

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.0085

T;T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.57

T;.;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.8

L;.;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.3

N;N;.

REVEL

Benign

0.21

Sift

Benign

0.26

T;T;.

Sift4G

Benign

0.12

T;T;.

Polyphen

0.74

P;.;.

Vest4

0.20

MutPred

0.35

Loss of catalytic residue at V432 (P = 0.0892);.;Loss of catalytic residue at V432 (P = 0.0892);

MVP

0.24

ClinPred

0.040

GERP RS

0.20

Varity_R

0.056

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

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