X-8795284-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_174951.3(FAM9A):​c.625G>A​(p.Ala209Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000334 in 1,196,686 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A209S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: FAM9A NM_174951.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.195
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.105050564).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174951.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM9A	NM_174951.3	MANE Select	c.625G>A	p.Ala209Thr	missense	Exon 7 of 10	NP_777611.1	Q8IZU1
	FAM9A	NM_001171186.1		c.625G>A	p.Ala209Thr	missense	Exon 7 of 10	NP_001164657.1	Q8IZU1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM9A	ENST00000381003.7	TSL:1 MANE Select	c.625G>A	p.Ala209Thr	missense	Exon 7 of 10	ENSP00000370391.3	Q8IZU1
	FAM9A	ENST00000543214.1	TSL:1	c.625G>A	p.Ala209Thr	missense	Exon 7 of 10	ENSP00000440163.1	Q8IZU1

Frequencies

GnomAD3 genomes AF: 0.00000914 AC: 1 AN: 109443 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000334

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 2 AN: 167005 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000771

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 3 AN: 1087243 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 1 AN XY: 356785

African (AFR) AF: 0.00 AC: 0 AN: 26075

American (AMR) AF: 0.00 AC: 0 AN: 34591

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19335

East Asian (EAS) AF: 0.00 AC: 0 AN: 29719

South Asian (SAS) AF: 0.00 AC: 0 AN: 53497

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3082

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 837160

Other (OTH) AF: 0.0000439 AC: 2 AN: 45528

GnomAD4 genome AF: 0.00000914 AC: 1 AN: 109443 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32157

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000334 AC: 1 AN: 29903

American (AMR) AF: 0.00 AC: 0 AN: 10015

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2625

East Asian (EAS) AF: 0.00 AC: 0 AN: 3433

South Asian (SAS) AF: 0.00 AC: 0 AN: 2498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52714

Other (OTH) AF: 0.00 AC: 0 AN: 1464

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000836 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.3
DANN	Benign	0.87
DEOGEN2	Benign	0.0096	T
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.00049	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.20
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.041
Sift	Benign	0.079	T
Sift4G	Benign	0.095	T
Polyphen		0.88	P
Vest4		0.17
MutPred		0.31		Gain of phosphorylation at A209 (P = 0.0174)
MVP		0.50
MPC		0.052
ClinPred		0.092	T
Varity_R		0.076
gMVP		0.016
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs778307732; hg19: chrX-8763325;