X-8791359-G-T

Variant names:

• chrX-8791359-G-T
• NM_174951.3:c.951C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_174951.3(FAM9A):​c.951C>A​(p.Asp317Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000917 in 1,090,321 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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • 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: -1.13

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050036192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM9A	NM_174951.3	c.951C>A	p.Asp317Glu	missense_variant	Exon 9 of 10	ENST00000381003.7	NP_777611.1
FAM9A	NM_001171186.1	c.951C>A	p.Asp317Glu	missense_variant	Exon 9 of 10		NP_001164657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM9A	ENST00000381003.7	c.951C>A	p.Asp317Glu	missense_variant	Exon 9 of 10	1	NM_174951.3	ENSP00000370391.3
FAM9A	ENST00000543214.1	c.951C>A	p.Asp317Glu	missense_variant	Exon 9 of 10	1		ENSP00000440163.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.17e-7 AC: 1 AN: 1090321 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 356511

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.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.951C>A (p.D317E) alteration is located in exon 9 (coding exon 8) of the FAM9A gene. This alteration results from a C to A substitution at nucleotide position 951, causing the aspartic acid (D) at amino acid position 317 to be replaced by a glutamic acid (E). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.0
DANN	Benign	0.96
DEOGEN2	Benign	0.0043	T;T
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.24	T;.
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L
PROVEAN	Benign	-0.54	N;N
REVEL	Benign	0.035
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		0.018	B;B
Vest4		0.12
MutPred		0.20		Loss of phosphorylation at Y319 (P = 0.0979);Loss of phosphorylation at Y319 (P = 0.0979);
MVP		0.099
MPC		0.051
ClinPred		0.059	T
GERP RS		-1.0
Varity_R		0.29
gMVP		0.0044

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-8759400;