X-8795284-C-A

Variant names:

• chrX-8795284-C-A
• rs778307732
• NM_174951.3:c.625G>T

Variant summary

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

The NM_174951.3(FAM9A):​c.625G>T​(p.Ala209Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000092 in 1,087,243 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: FAM9A NM_174951.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.195

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=0.10613379).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM9A	NM_174951.3	c.625G>T	p.Ala209Ser	missense_variant	Exon 7 of 10	ENST00000381003.7	NP_777611.1
FAM9A	NM_001171186.1	c.625G>T	p.Ala209Ser	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.625G>T	p.Ala209Ser	missense_variant	Exon 7 of 10	1	NM_174951.3	ENSP00000370391.3
FAM9A	ENST00000543214.1	c.625G>T	p.Ala209Ser	missense_variant	Exon 7 of 10	1		ENSP00000440163.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD3 exomes AF: 0.00000599 AC: 1 AN: 167005 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 57345

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: 0.0000138

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.20e-7 AC: 1 AN: 1087243 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 356785

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

Bravo AF: 0.00000756

ExAC AF: 0.00000836 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.625G>T (p.A209S) alteration is located in exon 7 (coding exon 6) of the FAM9A gene. This alteration results from a G to T substitution at nucleotide position 625, causing the alanine (A) at amino acid position 209 to be replaced by a serine (S). 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	0.34
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.2
DANN	Benign	0.95
DEOGEN2	Benign	0.0093	T;T
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.21	T;.
M_CAP	Benign	0.00059	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PROVEAN	Benign	0.24	N;N
REVEL	Benign	0.059
Sift	Benign	0.061	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.76	P;P
Vest4		0.14
MVP		0.43
MPC		0.050
ClinPred		0.096	T
Varity_R		0.14
gMVP		0.012

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: rs778307732; hg19: chrX-8763325;