X-8791372-T-C

Variant summary

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

The NM_174951.3(FAM9A):​c.938A>G​(p.Lys313Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 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. K313E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Consequence

FAM9A
NM_174951.3 missense

Scores

1
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.847
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]

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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=0.057385445).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FAM9ANM_174951.3 linkc.938A>G p.Lys313Arg missense_variant Exon 9 of 10 ENST00000381003.7 NP_777611.1 Q8IZU1
FAM9ANM_001171186.1 linkc.938A>G p.Lys313Arg missense_variant Exon 9 of 10 NP_001164657.1 Q8IZU1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FAM9AENST00000381003.7 linkc.938A>G p.Lys313Arg missense_variant Exon 9 of 10 1 NM_174951.3 ENSP00000370391.3 Q8IZU1
FAM9AENST00000543214.1 linkc.938A>G p.Lys313Arg missense_variant Exon 9 of 10 1 ENSP00000440163.1 Q8IZU1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
23

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 15, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.938A>G (p.K313R) alteration is located in exon 9 (coding exon 8) of the FAM9A gene. This alteration results from a A to G substitution at nucleotide position 938, causing the lysine (K) at amino acid position 313 to be replaced by an arginine (R). 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
0.12
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.96
CADD
Benign
6.2
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0074
T;T
FATHMM_MKL
Benign
0.0037
N
LIST_S2
Benign
0.31
T;.
M_CAP
Benign
0.0011
T
MetaRNN
Benign
0.057
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.55
N;N
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.10
Sift
Benign
0.39
T;T
Sift4G
Benign
0.23
T;T
Polyphen
0.0010
B;B
Vest4
0.074
MutPred
0.17
Loss of ubiquitination at K313 (P = 0.0224);Loss of ubiquitination at K313 (P = 0.0224);
MVP
0.12
MPC
0.047
ClinPred
0.082
T
GERP RS
-0.73
Varity_R
0.085
gMVP
0.0054

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-8759413; API