Genetic Variant FAM120C:p.Arg1093Trp (chrX-54073047-G-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_017848.6(FAM120C):c.3277C>T(p.Arg1093Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000666 in 1,201,762 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1093P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000068 ( 0 hom. 22 hem. )

Consequence

FAM120C
NM_017848.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.53

Variant links:

Genes affected

FAM120C (HGNC:16949): (family with sequence similarity 120 member C) This gene encodes a potential transmembrane protein and lies in a region where mutations and deletions have been associated with intellectual disability and autism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

FAM120C links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12491611).

BS2

High Hemizygotes in GnomAdExome4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM120C	NM_017848.6 link	c.3277C>T	p.Arg1093Trp	missense_variant	Exon 16 of 16	ENST00000375180.7	NP_060318.4	Q9NX05-1
FAM120C	NM_001300788.2 link	c.*177C>T		3_prime_UTR_variant	Exon 14 of 14		NP_001287717.1	F8W881

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM120C	ENST00000375180.7 link	c.3277C>T	p.Arg1093Trp	missense_variant	Exon 16 of 16	1	NM_017848.6	ENSP00000364324.2		Q9NX05-1
FAM120C	ENST00000328235 link	c.*177C>T		3_prime_UTR_variant	Exon 14 of 14	1		ENSP00000329896.4		F8W881

Frequencies

GnomAD3 genomes

AF:

0.0000537

AC:

AN:

111652

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33854

show subpopulations

Gnomad AFR

AF:

0.0000975

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000169

AC:

AN:

177409

Hom.:

AF XY:

0.0000321

AC XY:

AN XY:

62225

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:

0.0000579

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000250

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000679

AC:

AN:

1090110

Hom.:

Cov.:

AF XY:

0.0000617

AC XY:

AN XY:

356348

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000190

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000836

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000537

AC:

AN:

111652

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33854

show subpopulations

Gnomad4 AFR

AF:

0.0000975

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000279

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000377

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3277C>T (p.R1093W) alteration is located in exon 16 (coding exon 16) of the FAM120C gene. This alteration results from a C to T substitution at nucleotide position 3277, causing the arginine (R) at amino acid position 1093 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

Benign

0.085

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Uncertain

1.0

FATHMM_MKL

Benign

0.76

M_CAP

Benign

0.044

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.7

REVEL

Benign

0.13

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.013

Vest4

0.033

MutPred

0.20

Loss of methylation at K1094 (P = 0.0669);

MVP

0.23

MPC

1.2

ClinPred

0.57

GERP RS

3.2

gMVP

0.17

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