Genetic Variant FAM9A:c.489-3C>T (chrX-8795423-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_174951.3(FAM9A):c.489-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00689 in 1,181,120 control chromosomes in the GnomAD database, including 21 homozygotes. There are 2,632 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 1 hom., 190 hem., cov: 22)

Exomes 𝑓: 0.0071 ( 20 hom. 2442 hem. )

Consequence

FAM9A
NM_174951.3 splice_region, intron

Scores

Splicing: ADA: 0.0005165

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0420

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 made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant X-8795423-G-A is Benign according to our data. Variant chrX-8795423-G-A is described in ClinVar as [Benign]. Clinvar id is 789363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 190 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM9A	NM_174951.3 link	c.489-3C>T		splice_region_variant, intron_variant	Intron 6 of 9	ENST00000381003.7	NP_777611.1	Q8IZU1
FAM9A	NM_001171186.1 link	c.489-3C>T		splice_region_variant, intron_variant	Intron 6 of 9		NP_001164657.1	Q8IZU1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM9A	ENST00000381003.7 link	c.489-3C>T		splice_region_variant, intron_variant	Intron 6 of 9	1	NM_174951.3	ENSP00000370391.3		Q8IZU1
FAM9A	ENST00000543214.1 link	c.489-3C>T		splice_region_variant, intron_variant	Intron 6 of 9	1		ENSP00000440163.1		Q8IZU1

Frequencies

GnomAD3 genomes

AF:

0.00519

AC:

580

AN:

111669

Hom.:

Cov.:

AF XY:

0.00561

AC XY:

190

AN XY:

33841

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00566

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000375

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.0294

Gnomad NFE

AF:

0.00751

Gnomad OTH

AF:

0.00469

GnomAD3 exomes

AF:

0.00549

AC:

909

AN:

165488

Hom.:

AF XY:

0.00547

AC XY:

296

AN XY:

54126

show subpopulations

Gnomad AFR exome

AF:

0.000770

Gnomad AMR exome

AF:

0.00393

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.0144

Gnomad NFE exome

AF:

0.00731

Gnomad OTH exome

AF:

0.00520

GnomAD4 exome

AF:

0.00707

AC:

7564

AN:

1069398

Hom.:

Cov.:

AF XY:

0.00715

AC XY:

2442

AN XY:

341732

show subpopulations

Gnomad4 AFR exome

AF:

0.000862

Gnomad4 AMR exome

AF:

0.00434

Gnomad4 ASJ exome

AF:

0.000109

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.0157

Gnomad4 NFE exome

AF:

0.00774

Gnomad4 OTH exome

AF:

0.00657

GnomAD4 genome

AF:

0.00517

AC:

578

AN:

111722

Hom.:

Cov.:

AF XY:

0.00560

AC XY:

190

AN XY:

33904

show subpopulations

Gnomad4 AFR

AF:

0.00114

Gnomad4 AMR

AF:

0.00566

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000376

Gnomad4 FIN

AF:

0.0118

Gnomad4 NFE

AF:

0.00751

Gnomad4 OTH

AF:

0.00463

Alfa

AF:

0.00578

Hom.:

Bravo

AF:

0.00432

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 14, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

4.1

DANN

Benign

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00052

dbscSNV1_RF

Benign

0.11

SpliceAI score (max)

0.030

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