X-8798159-G-A

Variant names:

• chrX-8798159-G-A
• rs745777995
• NM_174951.3:c.364C>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_174951.3(FAM9A):​c.364C>T​(p.His122Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000565 in 1,203,243 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000060 (0 hom. 25 hem.)
• Consequence: FAM9A NM_174951.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.77

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020158231).
• BP6: Variant X-8798159-G-A is Benign according to our data. Variant chrX-8798159-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3512589.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 25 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM9A	NM_174951.3	c.364C>T	p.His122Tyr	missense_variant	Exon 5 of 10	ENST00000381003.7	NP_777611.1
FAM9A	NM_001171186.1	c.364C>T	p.His122Tyr	missense_variant	Exon 5 of 10		NP_001164657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM9A	ENST00000381003.7	c.364C>T	p.His122Tyr	missense_variant	Exon 5 of 10	1	NM_174951.3	ENSP00000370391.3
FAM9A	ENST00000543214.1	c.364C>T	p.His122Tyr	missense_variant	Exon 5 of 10	1		ENSP00000440163.1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112122 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34292

Gnomad AFR AF: 0.00

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: 0.0000563

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000893 AC: 15 AN: 168005 Hom.: 0 AF XY: 0.0000554 AC XY: 3 AN XY: 54173

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: 0.0000649

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000596 AC: 65 AN: 1091121 Hom.: 0 Cov.: 29 AF XY: 0.0000699 AC XY: 25 AN XY: 357403

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: 0.0000496

Gnomad4 NFE exome AF: 0.0000728

Gnomad4 OTH exome AF: 0.0000436

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112122 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000563

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.0000302

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 24, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.65
DANN	Benign	0.18
DEOGEN2	Benign	0.013	T;T
FATHMM_MKL	Benign	0.00019	N
LIST_S2	Benign	0.30	T;.
M_CAP	Benign	0.00041	T
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N;N
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.020
Sift	Benign	0.64	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.081
MutPred		0.34		Gain of phosphorylation at H122 (P = 0.0343);Gain of phosphorylation at H122 (P = 0.0343);
MVP		0.21
MPC		0.060
ClinPred		0.014	T
GERP RS		-1.8
Varity_R		0.10
gMVP		0.020

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs745777995; hg19: chrX-8766200;