Genetic Variant FAM9C:p.Ile88Thr (chrX-13040824-A-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_174901.6(FAM9C):c.263T>C(p.Ile88Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000926 in 1,080,220 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000093 ( 0 hom. 5 hem. )

Consequence

FAM9C
NM_174901.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.217

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.064166516).

BP6

Variant X-13040824-A-G is Benign according to our data. Variant chrX-13040824-A-G is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM9C	NM_174901.6 link	c.263T>C	p.Ile88Thr	missense_variant	Exon 5 of 8	ENST00000380625.8	NP_777561.1	Q8IZT9A0A024RBW5
FAM9C	XM_024452348.2 link	c.575T>C	p.Ile192Thr	missense_variant	Exon 5 of 7		XP_024308116.2
FAM9C	XM_005274460.4 link	c.263T>C	p.Ile88Thr	missense_variant	Exon 5 of 8		XP_005274517.1	Q8IZT9A0A024RBW5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM9C	ENST00000380625.8 link	c.263T>C	p.Ile88Thr	missense_variant	Exon 5 of 8	1	NM_174901.6	ENSP00000369999.3		Q8IZT9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000125

AC:

AN:

160586

Hom.:

AF XY:

0.00

AC XY:

AN XY:

48724

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:

0.000138

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000926

AC:

AN:

1080220

Hom.:

Cov.:

AF XY:

0.0000143

AC XY:

AN XY:

349244

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:

0.000201

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.263T>C (p.I88T) alteration is located in exon 5 (coding exon 4) of the FAM9C gene. This alteration results from a T to C substitution at nucleotide position 263, causing the isoleucine (I) at amino acid position 88 to be replaced by a threonine (T). 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

0.18

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.3

DANN

Benign

0.19

DEOGEN2

Benign

0.036

T;T

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.33

.;T

M_CAP

Benign

0.0016

MetaRNN

Benign

0.064

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.23

N;N

REVEL

Benign

0.012

Sift

Benign

0.29

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.0030

B;B

Vest4

0.16

MutPred

0.41

Loss of methylation at K90 (P = 0.0577);Loss of methylation at K90 (P = 0.0577);

MVP

0.54

MPC

0.013

ClinPred

0.038

GERP RS

0.59

Varity_R

0.080

gMVP

0.047

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

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