X-8791372-T-C

Variant names:

• chrX-8791372-T-C
• NM_174951.3:c.938A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.847

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]

ACMG classification

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
FAM9A	NM_174951.3	c.938A>G	p.Lys313Arg	missense_variant	Exon 9 of 10	ENST00000381003.7	NP_777611.1
FAM9A	NM_001171186.1	c.938A>G	p.Lys313Arg	missense_variant	Exon 9 of 10		NP_001164657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM9A	ENST00000381003.7	c.938A>G	p.Lys313Arg	missense_variant	Exon 9 of 10	1	NM_174951.3	ENSP00000370391.3
FAM9A	ENST00000543214.1	c.938A>G	p.Lys313Arg	missense_variant	Exon 9 of 10	1		ENSP00000440163.1

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

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;