chr7-23689298-C-T

Variant summary

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

The NM_199136.5(FAM221A):​c.269C>T​(p.Ala90Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000262 in 1,564,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A90T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

FAM221A
NM_199136.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.14
Variant links:
Genes affected
FAM221A (HGNC:27977): (family with sequence similarity 221 member A)

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=0.021630943).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FAM221ANM_199136.5 linkc.269C>T p.Ala90Val missense_variant Exon 3 of 7 ENST00000344962.9 NP_954587.2 A4D161-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FAM221AENST00000344962.9 linkc.269C>T p.Ala90Val missense_variant Exon 3 of 7 1 NM_199136.5 ENSP00000342576.4 A4D161-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152114
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000240
AC:
6
AN:
250488
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135404
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000441
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000262
AC:
37
AN:
1412078
Hom.:
0
Cov.:
31
AF XY:
0.0000216
AC XY:
15
AN XY:
694704
show subpopulations
Gnomad4 AFR exome
AF:
0.0000610
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000244
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000289
Gnomad4 OTH exome
AF:
0.0000345
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152114
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000774
Hom.:
0
Bravo
AF:
0.0000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 09, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.269C>T (p.A90V) alteration is located in exon 3 (coding exon 3) of the FAM221A gene. This alteration results from a C to T substitution at nucleotide position 269, causing the alanine (A) at amino acid position 90 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
Benign
0.070
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.81
CADD
Benign
0.040
DANN
Benign
0.76
DEOGEN2
Benign
0.0010
.;T;T;.
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.032
N
LIST_S2
Benign
0.27
T;T;T;T
M_CAP
Benign
0.0045
T
MetaRNN
Benign
0.022
T;T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
-1.8
N;N;.;.
PrimateAI
Benign
0.25
T
PROVEAN
Benign
0.39
N;N;N;N
REVEL
Benign
0.0080
Sift
Benign
0.39
T;T;T;T
Sift4G
Benign
0.33
T;T;T;T
Polyphen
0.0
B;B;.;B
Vest4
0.14
MVP
0.040
MPC
0.072
ClinPred
0.014
T
GERP RS
-1.8
Varity_R
0.014
gMVP
0.10

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.

Other links and lift over

dbSNP: rs767498587; hg19: chr7-23728917; COSMIC: COSV105911970; API