Genetic Variant FAM227A:p.Ala521Thr (chr22-38591512-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001013647.2(FAM227A):c.1561G>A(p.Ala521Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000646 in 1,547,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000065 ( 0 hom. )

Consequence

FAM227A
NM_001013647.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.387

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.014972866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM227A	NM_001013647.2 link	c.1561G>A	p.Ala521Thr	missense_variant	Exon 16 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.1561G>A	p.Ala521Thr	missense_variant	Exon 16 of 17	5	NM_001013647.2	ENSP00000445093.1	F5H4B4-1
FAM227A	ENST00000355830.11 link	c.1561G>A	p.Ala521Thr	missense_variant	Exon 16 of 19	5		ENSP00000348086.7	A0A0A0MRD0
FAM227A	ENST00000540952.6 link	c.1561G>A	p.Ala521Thr	missense_variant	Exon 16 of 17	5		ENSP00000493504.1	A0A2R8YCE3
FAM227A	ENST00000544346.5 link	n.1879G>A		non_coding_transcript_exon_variant	Exon 16 of 16	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000645

AC:

AN:

1394914

Hom.:

Cov.:

AF XY:

0.0000102

AC XY:

AN XY:

687886

show subpopulations

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:

0.0000511

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000464

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000402

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1561G>A (p.A521T) alteration is located in exon 16 (coding exon 15) of the FAM227A gene. This alteration results from a G to A substitution at nucleotide position 1561, causing the alanine (A) at amino acid position 521 to be replaced by a threonine (T). 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

0.096

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.65

CADD

Benign

3.7

DANN

Benign

0.83

DEOGEN2

Benign

0.0049

T;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0085

LIST_S2

Benign

0.57

T;.;T

M_CAP

Benign

0.0066

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.52

N;N;.

REVEL

Benign

0.0080

Sift

Benign

0.28

T;T;.

Sift4G

Benign

0.49

T;T;.

Polyphen

0.037

B;.;.

Vest4

0.12

MutPred

0.20

Gain of phosphorylation at A521 (P = 0.0062);.;Gain of phosphorylation at A521 (P = 0.0062);

MVP

0.014

ClinPred

0.075

GERP RS

-6.2

Varity_R

0.031

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