22-38599770-C-T

Variant summary

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

The NM_001013647.2(FAM227A):​c.1373G>A​(p.Ser458Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000406 in 1,550,854 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 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

FAM227A
NM_001013647.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.103
Variant links:
Genes affected
FAM227A (HGNC:44197): (family with sequence similarity 227 member A)

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=0.08970514).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FAM227ANM_001013647.2 linkc.1373G>A p.Ser458Asn missense_variant Exon 14 of 17 ENST00000535113.7 NP_001013669.1 F5H4B4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FAM227AENST00000535113.7 linkc.1373G>A p.Ser458Asn missense_variant Exon 14 of 17 5 NM_001013647.2 ENSP00000445093.1 F5H4B4-1
FAM227AENST00000355830.11 linkc.1373G>A p.Ser458Asn missense_variant Exon 14 of 19 5 ENSP00000348086.7 A0A0A0MRD0
FAM227AENST00000540952.6 linkc.1373G>A p.Ser458Asn missense_variant Exon 14 of 17 5 ENSP00000493504.1 A0A2R8YCE3

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152098
Hom.:
0
Cov.:
31
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:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000837
AC:
13
AN:
155402
Hom.:
0
AF XY:
0.000134
AC XY:
11
AN XY:
82324
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000237
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000309
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000665
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000408
AC:
57
AN:
1398756
Hom.:
0
Cov.:
31
AF XY:
0.0000464
AC XY:
32
AN XY:
689880
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000119
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000215
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000287
Gnomad4 OTH exome
AF:
0.0000863
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152098
Hom.:
0
Cov.:
31
AF XY:
0.0000673
AC XY:
5
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000790
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 19, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1373G>A (p.S458N) alteration is located in exon 14 (coding exon 13) of the FAM227A gene. This alteration results from a G to A substitution at nucleotide position 1373, causing the serine (S) at amino acid position 458 to be replaced by an asparagine (N). 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
0.10
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
2.3
DANN
Benign
0.57
DEOGEN2
Benign
0.0053
T;T;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.015
N
LIST_S2
Benign
0.30
T;.;T
M_CAP
Benign
0.074
D
MetaRNN
Benign
0.090
T;T;T
MetaSVM
Benign
-0.76
T
MutationAssessor
Benign
0.90
L;.;.
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.87
N;N;.
REVEL
Benign
0.15
Sift
Benign
0.19
T;T;.
Sift4G
Benign
0.46
T;T;.
Polyphen
0.30
B;.;.
Vest4
0.10
MVP
0.13
ClinPred
0.027
T
GERP RS
-7.2
Varity_R
0.070

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs760878269; hg19: chr22-38995775; API