X-8795160-T-C

Variant names:

• chrX-8795160-T-C
• rs778086718
• NM_174951.3:c.749A>G

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.749A>G​(p.Glu250Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000293 in 1,023,407 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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000019 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000011 (0 hom. 0 hem.)
• Consequence: FAM9A NM_174951.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.794
• 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=0.11192709).

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.749A>G	p.Glu250Gly	missense	Exon 7 of 10	NP_777611.1	Q8IZU1
	FAM9A	NM_001171186.1		c.749A>G	p.Glu250Gly	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.749A>G	p.Glu250Gly	missense	Exon 7 of 10	ENSP00000370391.3	Q8IZU1
	FAM9A	ENST00000543214.1	TSL:1	c.749A>G	p.Glu250Gly	missense	Exon 7 of 10	ENSP00000440163.1	Q8IZU1

Frequencies

GnomAD3 genomes AF: 0.0000185 AC: 2 AN: 107886 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000677

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: 0.00 AC: 0 AN: 115129 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000109 AC: 1 AN: 915521 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 244909

African (AFR) AF: 0.00 AC: 0 AN: 22676

American (AMR) AF: 0.00 AC: 0 AN: 29338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17609

East Asian (EAS) AF: 0.00 AC: 0 AN: 27551

South Asian (SAS) AF: 0.00 AC: 0 AN: 45884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3725

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 696506

Other (OTH) AF: 0.0000250 AC: 1 AN: 39962

GnomAD4 genome AF: 0.0000185 AC: 2 AN: 107886 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 30692

African (AFR) AF: 0.0000677 AC: 2 AN: 29542

American (AMR) AF: 0.00 AC: 0 AN: 9954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2602

East Asian (EAS) AF: 0.00 AC: 0 AN: 3431

South Asian (SAS) AF: 0.00 AC: 0 AN: 2346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52034

Other (OTH) AF: 0.00 AC: 0 AN: 1446

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000178 AC: 2

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	Benign	0.088
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.20
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.00094	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.79
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.079
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.031	D
Polyphen		0.87	P
Vest4		0.25
MVP		0.22
MPC		0.061
ClinPred		0.18	T
GERP RS		-1.0
Varity_R		0.16
gMVP		0.033
Mutation Taster		=100/0	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: rs778086718; hg19: chrX-8763201; COSMIC: COSV101121315;