Genetic Variant FAM9C:p.Gly61Trp (chrX-13043129-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_174901.6(FAM9C):c.181G>T(p.Gly61Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,204,740 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000017 ( 0 hom. 7 hem. )

Consequence

FAM9C
NM_174901.6 missense, splice_region

Scores

Splicing: ADA: 0.0001786

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.733

Variant links:

Genes affected

FAM9C (HGNC:18405): (family with sequence similarity 9 member C) This gene is a member of a gene family which arose through duplication on the X chromosome. The encoded protein may be localized to the nucleus as the protein contains several nuclear localization signals, and has similarity to a synaptonemal complex protein. [provided by RefSeq, Aug 2011]

FAM9C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23779765).

BS2

High Hemizygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM9C	NM_174901.6 link	c.181G>T	p.Gly61Trp	missense_variant, splice_region_variant	Exon 3 of 8	ENST00000380625.8	NP_777561.1	Q8IZT9A0A024RBW5
FAM9C	XM_024452348.2 link	c.493G>T	p.Gly165Trp	missense_variant, splice_region_variant	Exon 3 of 7		XP_024308116.2
FAM9C	XM_005274460.4 link	c.181G>T	p.Gly61Trp	missense_variant, splice_region_variant	Exon 3 of 8		XP_005274517.1	Q8IZT9A0A024RBW5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM9C	ENST00000380625.8 link	c.181G>T	p.Gly61Trp	missense_variant, splice_region_variant	Exon 3 of 8	1	NM_174901.6	ENSP00000369999.3		Q8IZT9

Frequencies

GnomAD3 genomes

AF:

0.0000535

AC:

AN:

112061

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34229

show subpopulations

Gnomad AFR

AF:

0.0000650

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:

0.0000752

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000230

AC:

AN:

173967

Hom.:

AF XY:

0.0000168

AC XY:

AN XY:

59607

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000507

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000174

AC:

AN:

1092679

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

359059

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000214

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000535

AC:

AN:

112061

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34229

show subpopulations

Gnomad4 AFR

AF:

0.0000650

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:

0.0000752

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.181G>T (p.G61W) alteration is located in exon 3 (coding exon 2) of the FAM9C gene. This alteration results from a G to T substitution at nucleotide position 181, causing the glycine (G) at amino acid position 61 to be replaced by a tryptophan (W). 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.15

T;T;T

FATHMM_MKL

Benign

0.0075

LIST_S2

Benign

0.72

T;.;T

M_CAP

Benign

0.0038

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

.;L;L

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-8.0

D;D;D

REVEL

Benign

0.070

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.35

MutPred

0.26

Loss of loop (P = 0.0603);Loss of loop (P = 0.0603);Loss of loop (P = 0.0603);

MVP

0.33

MPC

0.088

ClinPred

0.55

GERP RS

-0.99

Varity_R

0.27

gMVP

0.098

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00018

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: 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