Genetic Variant FAM9C:p.Thr163Ser (chrX-13038454-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_174901.6(FAM9C):c.488C>G(p.Thr163Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000332 in 1,204,490 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000034 ( 0 hom. 9 hem. )

Consequence

FAM9C
NM_174901.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.38

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04191658).

BS2

High Hemizygotes in GnomAdExome4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM9C	NM_174901.6 link	c.488C>G	p.Thr163Ser	missense_variant	Exon 7 of 8	ENST00000380625.8	NP_777561.1	Q8IZT9A0A024RBW5
FAM9C	XM_024452348.2 link	c.800C>G	p.Thr267Ser	missense_variant	Exon 7 of 7		XP_024308116.2
FAM9C	XM_005274460.4 link	c.488C>G	p.Thr163Ser	missense_variant	Exon 7 of 8		XP_005274517.1	Q8IZT9A0A024RBW5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM9C	ENST00000380625.8 link	c.488C>G	p.Thr163Ser	missense_variant	Exon 7 of 8	1	NM_174901.6	ENSP00000369999.3		Q8IZT9

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111957

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34147

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000284

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:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

175980

Hom.:

AF XY:

0.000115

AC XY:

AN XY:

61028

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000857

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:

0.00

Gnomad OTH exome

AF:

0.000231

GnomAD4 exome

AF:

0.0000339

AC:

AN:

1092533

Hom.:

Cov.:

AF XY:

0.0000251

AC XY:

AN XY:

359041

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000957

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:

0.00000119

Gnomad4 OTH exome

AF:

0.0000655

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111957

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34147

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000284

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.488C>G (p.T163S) alteration is located in exon 7 (coding exon 6) of the FAM9C gene. This alteration results from a C to G substitution at nucleotide position 488, causing the threonine (T) at amino acid position 163 to be replaced by a serine (S). 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

Benign

0.15

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.027

T;T

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.26

.;T

M_CAP

Benign

0.0021

MetaRNN

Benign

0.042

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.44

PROVEAN

Benign

0.10

N;N

REVEL

Benign

0.11

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

1.0

T;T

Polyphen

0.88

P;P

Vest4

0.20

MutPred

0.074

Loss of methylation at K161 (P = 0.1164);Loss of methylation at K161 (P = 0.1164);

MVP

0.055

MPC

0.044

ClinPred

0.13

GERP RS

0.23

Varity_R

0.19

gMVP

0.013

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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