X-8798414-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_174951.3(FAM9A):​c.286G>A​(p.Val96Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000314 in 1,210,634 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 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 (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)
Exomes 𝑓: 0.000034 ( 0 hom. 17 hem. )

Consequence

FAM9A
NM_174951.3 missense

Scores

1
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.301
Variant links:
Genes affected
FAM9A (HGNC:18403): (family with sequence similarity 9 member A) This gene is a member of a gene family which arose through duplication on the X chromosome. The encoded protein may be a nuclear protein that is localized to the nucleolus, and has some similarity to a synaptonemal complex protein. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Aug 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11770457).
BS2
High Hemizygotes in GnomAdExome4 at 17 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FAM9ANM_174951.3 linkc.286G>A p.Val96Ile missense_variant Exon 4 of 10 ENST00000381003.7 NP_777611.1 Q8IZU1
FAM9ANM_001171186.1 linkc.286G>A p.Val96Ile missense_variant Exon 4 of 10 NP_001164657.1 Q8IZU1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FAM9AENST00000381003.7 linkc.286G>A p.Val96Ile missense_variant Exon 4 of 10 1 NM_174951.3 ENSP00000370391.3 Q8IZU1
FAM9AENST00000543214.1 linkc.286G>A p.Val96Ile missense_variant Exon 4 of 10 1 ENSP00000440163.1 Q8IZU1

Frequencies

GnomAD3 genomes
AF:
0.00000889
AC:
1
AN:
112442
Hom.:
0
Cov.:
24
AF XY:
0.00
AC XY:
0
AN XY:
34582
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000337
AC:
37
AN:
1098192
Hom.:
0
Cov.:
31
AF XY:
0.0000468
AC XY:
17
AN XY:
363548
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000416
Gnomad4 OTH exome
AF:
0.0000434
GnomAD4 genome
AF:
0.00000889
AC:
1
AN:
112442
Hom.:
0
Cov.:
24
AF XY:
0.00
AC XY:
0
AN XY:
34582
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 20, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.286G>A (p.V96I) alteration is located in exon 4 (coding exon 3) of the FAM9A gene. This alteration results from a G to A substitution at nucleotide position 286, causing the valine (V) at amino acid position 96 to be replaced by an isoleucine (I). 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
0.14
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.70
CADD
Benign
2.9
DANN
Benign
0.92
DEOGEN2
Benign
0.018
T;T
FATHMM_MKL
Benign
0.0027
N
LIST_S2
Benign
0.78
T;.
M_CAP
Benign
0.0013
T
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.90
L;L
PROVEAN
Benign
-0.50
N;N
REVEL
Benign
0.037
Sift
Pathogenic
0.0
D;D
Sift4G
Benign
0.27
T;T
Polyphen
0.76
P;P
Vest4
0.30
MutPred
0.15
Gain of catalytic residue at V96 (P = 0.0452);Gain of catalytic residue at V96 (P = 0.0452);
MVP
0.30
MPC
0.19
ClinPred
0.38
T
GERP RS
0.21
Varity_R
0.29
gMVP
0.016

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: rs1293198041; hg19: chrX-8766455; API