Genetic Variant FAM120C:p.Arg683Gln (chrX-54132706-C-T) – 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.2048G>A(p.Arg683Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000299 in 1,202,075 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 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 (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000031 ( 0 hom. 10 hem. )

Consequence

FAM120C
NM_017848.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.17

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=0.09995386).

BS2

High Hemizygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM120C	NM_017848.6 link	c.2048G>A	p.Arg683Gln	missense_variant	Exon 9 of 16	ENST00000375180.7	NP_060318.4	Q9NX05-1
FAM120C	NM_001300788.2 link	c.2048G>A	p.Arg683Gln	missense_variant	Exon 9 of 14		NP_001287717.1	F8W881
FAM120C	XM_006724589.5 link	c.2048G>A	p.Arg683Gln	missense_variant	Exon 9 of 15		XP_006724652.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM120C	ENST00000375180.7 link	c.2048G>A	p.Arg683Gln	missense_variant	Exon 9 of 16	1	NM_017848.6	ENSP00000364324.2		Q9NX05-1
FAM120C	ENST00000328235.4 link	c.2048G>A	p.Arg683Gln	missense_variant	Exon 9 of 14	1		ENSP00000329896.4		F8W881

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111694

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33890

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000282

Gnomad SAS

AF:

0.000377

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000481

AC:

AN:

166479

Hom.:

AF XY:

0.0000191

AC XY:

AN XY:

52225

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000803

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000310

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000312

AC:

AN:

1090381

Hom.:

Cov.:

AF XY:

0.0000280

AC XY:

AN XY:

356507

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000589

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000997

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000334

Gnomad4 OTH exome

AF:

0.0000219

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111694

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33890

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000282

Gnomad4 SAS

AF:

0.000377

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

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 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2048G>A (p.R683Q) alteration is located in exon 9 (coding exon 9) of the FAM120C gene. This alteration results from a G to A substitution at nucleotide position 2048, causing the arginine (R) at amino acid position 683 to be replaced by a glutamine (Q). 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

0.17

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

1.0

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.88

.;D

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.024

Sift

Benign

0.11

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.74

.;P

Vest4

0.17

MutPred

0.29

Loss of MoRF binding (P = 0.0335);Loss of MoRF binding (P = 0.0335);

MVP

0.26

MPC

0.81

ClinPred

0.032

GERP RS

2.9

gMVP

0.48

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