X-8795287-C-G

Variant names:

• chrX-8795287-C-G
• rs201732308
• NM_174951.3:c.622G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_174951.3(FAM9A):​c.622G>C​(p.Glu208Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,083,655 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000028 (0 hom. 0 hem.)
• Consequence: FAM9A NM_174951.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.26

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07211524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM9A	NM_174951.3	c.622G>C	p.Glu208Gln	missense_variant	Exon 7 of 10	ENST00000381003.7	NP_777611.1
FAM9A	NM_001171186.1	c.622G>C	p.Glu208Gln	missense_variant	Exon 7 of 10		NP_001164657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM9A	ENST00000381003.7	c.622G>C	p.Glu208Gln	missense_variant	Exon 7 of 10	1	NM_174951.3	ENSP00000370391.3
FAM9A	ENST00000543214.1	c.622G>C	p.Glu208Gln	missense_variant	Exon 7 of 10	1		ENSP00000440163.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000602 AC: 1 AN: 166079 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 57307

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000139

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 3 AN: 1083655 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 352661

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.622G>C (p.E208Q) alteration is located in exon 7 (coding exon 6) of the FAM9A gene. This alteration results from a G to C substitution at nucleotide position 622, causing the glutamic acid (E) at amino acid position 208 to be replaced by a glutamine (Q). 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	0.32
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.74
DANN	Benign	0.75
DEOGEN2	Benign	0.0042	T;T
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.24	T;.
M_CAP	Benign	0.00055	T
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.069
Sift	Benign	0.39	T;T
Sift4G	Uncertain	0.019	D;D
Polyphen		0.77	P;P
Vest4		0.091
MutPred		0.28		Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);
MVP		0.17
MPC		0.053
ClinPred		0.098	T
Varity_R		0.18
gMVP		0.049

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

Other links and lift over

dbSNP: rs201732308; hg19: chrX-8763328;