Genetic Variant FAM120C:p.Gly976Val (chrX-54081373-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_017848.6(FAM120C):c.2927G>T(p.Gly976Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000663 in 1,206,293 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. 10/16 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: 21)

Exomes 𝑓: 0.0000055 ( 0 hom. 4 hem. )

Consequence

FAM120C
NM_017848.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59

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=0.16546762).

BS2

High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM120C	NM_017848.6 link	c.2927G>T	p.Gly976Val	missense_variant	Exon 14 of 16	ENST00000375180.7	NP_060318.4	Q9NX05-1
FAM120C	NM_001300788.2 link	c.2515G>T	p.Ala839Ser	missense_variant	Exon 12 of 14		NP_001287717.1	F8W881
FAM120C	XM_006724589.5 link	c.*107G>T		downstream_gene_variant			XP_006724652.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM120C	ENST00000375180.7 link	c.2927G>T	p.Gly976Val	missense_variant	Exon 14 of 16	1	NM_017848.6	ENSP00000364324.2		Q9NX05-1
FAM120C	ENST00000328235.4 link	c.2515G>T	p.Ala839Ser	missense_variant	Exon 12 of 14	1		ENSP00000329896.4		F8W881

Frequencies

GnomAD3 genomes

AF:

0.0000184

AC:

AN:

108870

Hom.:

Cov.:

AF XY:

0.0000321

AC XY:

AN XY:

31172

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

182791

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

67253

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:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1097423

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362791

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:

0.00000713

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000184

AC:

AN:

108870

Hom.:

Cov.:

AF XY:

0.0000321

AC XY:

AN XY:

31172

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000382

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 20, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2927G>T (p.G976V) alteration is located in exon 14 (coding exon 14) of the FAM120C gene. This alteration results from a G to T substitution at nucleotide position 2927, causing the glycine (G) at amino acid position 976 to be replaced by a valine (V). 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

0.21

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.99

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.43

M_CAP

Benign

0.024

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.86

PROVEAN

Benign

-0.49

REVEL

Benign

0.090

Sift

Pathogenic

0.0

Sift4G

Benign

0.14

Polyphen

0.010

Vest4

0.33

MutPred

0.21

Gain of glycosylation at A839 (P = 0.0192);

MVP

0.40

ClinPred

0.90

GERP RS

4.0

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