X-9027885-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_205849.3(FAM9B):​c.475C>T​(p.Arg159Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000538 in 1,207,570 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 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. R159H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 4 hem., cov: 22)
Exomes 𝑓: 0.000054 ( 0 hom. 32 hem. )

Consequence

FAM9B
NM_205849.3 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.535
Variant links:
Genes affected
FAM9B (HGNC:18404): (family with sequence similarity 9 member B) This gene is a member of a gene family which arose through duplication on the X chromosome. The encoded protein may be localized to the nucleus as the protein contains several nuclear localization signals, and has similarity to a synaptonemal complex protein. [provided by RefSeq, Aug 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.044690907).
BS2
High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FAM9BNM_205849.3 linkuse as main transcriptc.475C>T p.Arg159Cys missense_variant 7/9 ENST00000327220.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FAM9BENST00000327220.10 linkuse as main transcriptc.475C>T p.Arg159Cys missense_variant 7/91 NM_205849.3 P1Q8IZU0-1

Frequencies

GnomAD3 genomes
AF:
0.0000536
AC:
6
AN:
111860
Hom.:
0
Cov.:
22
AF XY:
0.000117
AC XY:
4
AN XY:
34058
show subpopulations
Gnomad AFR
AF:
0.0000325
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000739
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000376
Gnomad OTH
AF:
0.000664
GnomAD3 exomes
AF:
0.0000928
AC:
17
AN:
183182
Hom.:
0
AF XY:
0.000163
AC XY:
11
AN XY:
67680
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000365
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000579
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000611
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000538
AC:
59
AN:
1095657
Hom.:
0
Cov.:
28
AF XY:
0.0000886
AC XY:
32
AN XY:
361297
show subpopulations
Gnomad4 AFR exome
AF:
0.0000380
Gnomad4 AMR exome
AF:
0.0000284
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000611
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000262
Gnomad4 OTH exome
AF:
0.0000435
GnomAD4 genome
AF:
0.0000536
AC:
6
AN:
111913
Hom.:
0
Cov.:
22
AF XY:
0.000117
AC XY:
4
AN XY:
34121
show subpopulations
Gnomad4 AFR
AF:
0.0000324
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000742
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000376
Gnomad4 OTH
AF:
0.000655
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000659
AC:
8

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 06, 2023The c.475C>T (p.R159C) alteration is located in exon 6 (coding exon 6) of the FAM9B gene. This alteration results from a C to T substitution at nucleotide position 475, causing the arginine (R) at amino acid position 159 to be replaced by a cysteine (C). 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
0.23
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.033
.;T;T
FATHMM_MKL
Benign
0.010
N
LIST_S2
Benign
0.62
T;T;.
M_CAP
Benign
0.0013
T
MetaRNN
Benign
0.045
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
.;N;N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.9
N;N;N
REVEL
Benign
0.098
Sift
Benign
0.16
T;T;T
Sift4G
Benign
0.083
T;D;D
Polyphen
1.0
.;D;D
Vest4
0.13
MVP
0.38
MPC
0.39
ClinPred
0.31
T
GERP RS
-0.85
Varity_R
0.11

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: rs201073413; hg19: chrX-8995926; API