Genetic Variant FAM9A:p.Lys70Arg (chrX-8798977-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_174951.3(FAM9A):c.209A>G(p.Lys70Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,211,905 control chromosomes in the GnomAD database, including 2 homozygotes. There are 80 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 0.00088 ( 2 hom., 32 hem., cov: 24)

Exomes 𝑓: 0.00016 ( 0 hom. 48 hem. )

Consequence

FAM9A
NM_174951.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0140

Variant links:

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]

FAM9A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006012231).

BP6

Variant X-8798977-T-C is Benign according to our data. Variant chrX-8798977-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2659949.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM9A	NM_174951.3 link	c.209A>G	p.Lys70Arg	missense_variant	Exon 3 of 10	ENST00000381003.7	NP_777611.1	Q8IZU1
FAM9A	NM_001171186.1 link	c.209A>G	p.Lys70Arg	missense_variant	Exon 3 of 10		NP_001164657.1	Q8IZU1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM9A	ENST00000381003.7 link	c.209A>G	p.Lys70Arg	missense_variant	Exon 3 of 10	1	NM_174951.3	ENSP00000370391.3		Q8IZU1
FAM9A	ENST00000543214.1 link	c.209A>G	p.Lys70Arg	missense_variant	Exon 3 of 10	1		ENSP00000440163.1		Q8IZU1

Frequencies

GnomAD3 genomes

AF:

0.000871

AC:

AN:

113650

Hom.:

Cov.:

AF XY:

0.000894

AC XY:

AN XY:

35778

show subpopulations

Gnomad AFR

AF:

0.00300

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.0000374

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000267

AC:

AN:

183220

Hom.:

AF XY:

0.000222

AC XY:

AN XY:

67678

show subpopulations

Gnomad AFR exome

AF:

0.00266

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000110

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000158

AC:

174

AN:

1098202

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

363568

show subpopulations

Gnomad4 AFR exome

AF:

0.00242

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000106

Gnomad4 OTH exome

AF:

0.000260

GnomAD4 genome

AF:

0.000879

AC:

100

AN:

113703

Hom.:

Cov.:

AF XY:

0.000893

AC XY:

AN XY:

35841

show subpopulations

Gnomad4 AFR

AF:

0.00302

Gnomad4 AMR

AF:

0.000183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000374

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000151

Hom.:

Bravo

AF:

0.00103

ESP6500AA

AF:

0.00261

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000321

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FAM9A: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.91

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.0072

T;T

FATHMM_MKL

Benign

0.0019

LIST_S2

Benign

0.49

T;.

M_CAP

Benign

0.00091

MetaRNN

Benign

0.0060

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;N

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.096

Sift

Benign

0.15

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.97

D;D

Vest4

0.15

MVP

0.10

MPC

0.25

ClinPred

0.0078

GERP RS

-0.88

Varity_R

0.11

gMVP

0.030

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over