Genetic Variant FAM9A:p.Ala214Thr (chrX-8795269-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_174951.3(FAM9A):c.640G>A(p.Ala214Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,076,123 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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: not found (cov: 22)

Exomes 𝑓: 0.0000056 ( 0 hom. 3 hem. )

Consequence

FAM9A
NM_174951.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.268

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13003641).

BS2

High Hemizygotes in GnomAdExome4 at 3 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.640G>A	p.Ala214Thr	missense	Exon 7 of 10	NP_777611.1	Q8IZU1
	FAM9A	NM_001171186.1		c.640G>A	p.Ala214Thr	missense	Exon 7 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.640G>A	p.Ala214Thr	missense	Exon 7 of 10	ENSP00000370391.3	Q8IZU1
	FAM9A	ENST00000543214.1	TSL:1	c.640G>A	p.Ala214Thr	missense	Exon 7 of 10	ENSP00000440163.1	Q8IZU1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000655

AC:

AN:

152730

AF XY:

0.0000208

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000558

AC:

AN:

1076123

Hom.:

Cov.:

AF XY:

0.00000863

AC XY:

AN XY:

347617

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25840

American (AMR)

AF:

0.00

AC:

AN:

33726

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19233

East Asian (EAS)

AF:

0.00

AC:

AN:

29440

South Asian (SAS)

AF:

0.000114

AC:

AN:

52828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37339

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3149

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

829307

Other (OTH)

AF:

0.00

AC:

AN:

45261

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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

Cov.:

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

0.26

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.0

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.0075

FATHMM_MKL

Benign

0.0042

LIST_S2

Benign

0.27

M_CAP

Benign

0.00056

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.27

PROVEAN

Benign

-0.55

REVEL

Benign

0.026

Sift

Benign

0.087

Sift4G

Benign

0.48

Polyphen

0.88

Vest4

0.14

MutPred

0.26

Gain of loop (P = 0.0079)

MVP

0.59

MPC

0.052

ClinPred

0.11

GERP RS

0.15

Varity_R

0.12

gMVP

0.017

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over