Genetic Variant FAM9A:p.Pro68Leu (chrX-8798983-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_174951.3(FAM9A):c.203C>T(p.Pro68Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,211,727 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000032 ( 0 hom. 14 hem. )

Consequence

FAM9A
NM_174951.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.514

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016061544).

BS2

High Hemizygotes in GnomAdExome4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM9A	NM_174951.3 link	c.203C>T	p.Pro68Leu	missense_variant	Exon 3 of 10	ENST00000381003.7	NP_777611.1	Q8IZU1
FAM9A	NM_001171186.1 link	c.203C>T	p.Pro68Leu	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.203C>T	p.Pro68Leu	missense_variant	Exon 3 of 10	1	NM_174951.3	ENSP00000370391.3		Q8IZU1
FAM9A	ENST00000543214.1 link	c.203C>T	p.Pro68Leu	missense_variant	Exon 3 of 10	1		ENSP00000440163.1		Q8IZU1

Frequencies

GnomAD3 genomes

AF:

0.0000352

AC:

AN:

113506

Hom.:

Cov.:

AF XY:

0.0000281

AC XY:

AN XY:

35630

show subpopulations

Gnomad AFR

AF:

0.0000959

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:

0.0000187

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000327

AC:

AN:

183211

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

67683

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000319

AC:

AN:

1098167

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

363535

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.00

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:

0.0000321

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000352

AC:

AN:

113560

Hom.:

Cov.:

AF XY:

0.0000280

AC XY:

AN XY:

35694

show subpopulations

Gnomad4 AFR

AF:

0.0000956

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:

0.0000187

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.203C>T (p.P68L) alteration is located in exon 3 (coding exon 2) of the FAM9A gene. This alteration results from a C to T substitution at nucleotide position 203, causing the proline (P) at amino acid position 68 to be replaced by a leucine (L). 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

Benign

0.17

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.8

DANN

Benign

0.50

DEOGEN2

Benign

0.0059

T;T

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.42

T;.

M_CAP

Benign

0.0012

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PROVEAN

Benign

-0.99

N;N

REVEL

Benign

0.25

Sift

Benign

0.17

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.98

D;D

Vest4

0.13

MVP

0.10

MPC

0.34

ClinPred

0.038

GERP RS

-0.81

Varity_R

0.042

gMVP

0.020

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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