X-8795413-G-A

Variant names:

• chrX-8795413-G-A
• rs779704332
• NM_174951.3:c.496C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_174951.3(FAM9A):​c.496C>T​(p.Arg166Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,077,534 control chromosomes in the GnomAD database, including 1 homozygotes. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 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: 0.000014 (1 hom. 6 hem.)
• Consequence: FAM9A NM_174951.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14763689).
• BS2: High Hemizygotes in GnomAdExome4 at 6 gene

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.496C>T	p.Arg166Cys	missense	Exon 7 of 10	NP_777611.1	Q8IZU1
	FAM9A	NM_001171186.1		c.496C>T	p.Arg166Cys	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.496C>T	p.Arg166Cys	missense	Exon 7 of 10	ENSP00000370391.3	Q8IZU1
	FAM9A	ENST00000543214.1	TSL:1	c.496C>T	p.Arg166Cys	missense	Exon 7 of 10	ENSP00000440163.1	Q8IZU1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000294 AC: 5 AN: 170163 AF XY: 0.0000175

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000767

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 15 AN: 1077534 Hom.: 1 Cov.: 31 AF XY: 0.0000173 AC XY: 6 AN XY: 347612

African (AFR) AF: 0.00 AC: 0 AN: 25851

American (AMR) AF: 0.0000587 AC: 2 AN: 34098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18652

East Asian (EAS) AF: 0.00 AC: 0 AN: 29873

South Asian (SAS) AF: 0.000174 AC: 9 AN: 51747

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2849

European-Non Finnish (NFE) AF: 0.00000362 AC: 3 AN: 829237

Other (OTH) AF: 0.0000222 AC: 1 AN: 45107

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.7
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.061
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.029	D
Polyphen		0.99	D
Vest4		0.091
MutPred		0.26		Gain of methylation at K165 (P = 0.0514)
MVP		0.20
MPC		0.38
ClinPred		0.42	T
GERP RS		0.61
Varity_R		0.28
gMVP		0.088
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs779704332; hg19: chrX-8763454;