Genetic Variant NM_174951.3:c.436A>G (chrX-8796320-T-C) – 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.436A>G(p.Arg146Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000739 in 1,205,059 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., 19 hem., cov: 24)

Exomes 𝑓: 0.000043 ( 0 hom. 11 hem. )

Consequence

FAM9A
NM_174951.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.826

Publications

0 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=0.023919404).

BS2

High Hemizygotes in GnomAd4 at 19 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.436A>G	p.Arg146Gly	missense	Exon 6 of 10	NP_777611.1	Q8IZU1
	FAM9A	NM_001171186.1		c.436A>G	p.Arg146Gly	missense	Exon 6 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.436A>G	p.Arg146Gly	missense	Exon 6 of 10	ENSP00000370391.3	Q8IZU1
	FAM9A	ENST00000543214.1	TSL:1	c.436A>G	p.Arg146Gly	missense	Exon 6 of 10	ENSP00000440163.1	Q8IZU1

Frequencies

GnomAD3 genomes

AF:

0.000367

AC:

AN:

111657

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000285

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:

0.00

Gnomad OTH

AF:

0.000662

GnomAD2 exomes

AF:

0.0000861

AC:

AN:

174265

AF XY:

0.0000502

show subpopulations

Gnomad AFR exome

AF:

0.00101

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:

0.0000260

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000430

AC:

AN:

1093351

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

AN XY:

359529

show subpopulations

African (AFR)

AF:

0.00141

AC:

AN:

26276

American (AMR)

AF:

0.0000287

AC:

AN:

34794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19312

East Asian (EAS)

AF:

0.00

AC:

AN:

30075

South Asian (SAS)

AF:

0.00

AC:

AN:

53109

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.00000357

AC:

AN:

839433

Other (OTH)

AF:

0.000131

AC:

AN:

45906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.000376

AC:

AN:

111708

Hom.:

Cov.:

AF XY:

0.000561

AC XY:

AN XY:

33884

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

30783

American (AMR)

AF:

0.000285

AC:

AN:

10521

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3581

South Asian (SAS)

AF:

0.00

AC:

AN:

2662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53075

Other (OTH)

AF:

0.000654

AC:

AN:

1530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000457

ExAC

AF:

0.000107

AC:

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

Uncertain

0.47

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.62

CADD

Benign

7.5

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.094

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.40

M_CAP

Benign

0.0012

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.83

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.12

Sift

Benign

0.079

Sift4G

Benign

0.38

Polyphen

0.94

Vest4

0.17

MutPred

0.33

Loss of helix (P = 0.0237)

MVP

0.15

MPC

0.29

ClinPred

0.091

GERP RS

-1.2

Varity_R

0.21

gMVP

0.035

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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