Genetic Variant NM_174951.3:c.203C>T (chrX-8798983-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000035 ( 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

Publications

1 publications found

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 was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

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

BS2

High Hemizygotes in GnomAdExome4 at 14 gene

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.203C>T	p.Pro68Leu	missense	Exon 3 of 10	NP_777611.1	Q8IZU1
	FAM9A	NM_001171186.1		c.203C>T	p.Pro68Leu	missense	Exon 3 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.203C>T	p.Pro68Leu	missense	Exon 3 of 10	ENSP00000370391.3	Q8IZU1
	FAM9A	ENST00000543214.1	TSL:1	c.203C>T	p.Pro68Leu	missense	Exon 3 of 10	ENSP00000440163.1	Q8IZU1

Frequencies

GnomAD3 genomes

AF:

0.0000352

AC:

AN:

113506

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000327

AC:

AN:

183211

AF XY:

0.0000443

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 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

African (AFR)

AF:

0.000152

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54143

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000321

AC:

AN:

842083

Other (OTH)

AF:

0.0000651

AC:

AN:

46092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000352

AC:

AN:

113560

Hom.:

Cov.:

AF XY:

0.0000280

AC XY:

AN XY:

35694

show subpopulations

African (AFR)

AF:

0.0000956

AC:

AN:

31366

American (AMR)

AF:

0.00

AC:

AN:

10889

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2661

East Asian (EAS)

AF:

0.00

AC:

AN:

3577

South Asian (SAS)

AF:

0.00

AC:

AN:

2831

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000187

AC:

AN:

53428

Other (OTH)

AF:

0.00

AC:

AN:

1556

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.8

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.0059

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.42

M_CAP

Benign

0.0012

MetaRNN

Benign

0.016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.51

PROVEAN

Benign

-0.99

REVEL

Benign

0.25

Sift

Benign

0.17

Sift4G

Benign

0.14

Polyphen

0.98

Vest4

0.13

MVP

0.10

MPC

0.34

ClinPred

0.038

GERP RS

-0.81

Varity_R

0.042

gMVP

0.020

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over