X-54081347-C-T

Variant names:

• chrX-54081347-C-T
• rs2066763921
• ENST00000328235.4:c.2541G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001300788.2(FAM120C):​c.2541G>A​(p.Trp847*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 21)
• Consequence: FAM120C NM_001300788.2 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.53

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM120C	NM_017848.6	c.2953G>A	p.Val985Ile	missense_variant	Exon 14 of 16	ENST00000375180.7	NP_060318.4
FAM120C	NM_001300788.2	c.2541G>A	p.Trp847*	stop_gained	Exon 12 of 14		NP_001287717.1
FAM120C	XM_006724589.5	c.*133G>A		downstream_gene_variant			XP_006724652.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM120C	ENST00000328235.4	c.2541G>A	p.Trp847*	stop_gained	Exon 12 of 14	1		ENSP00000329896.4
FAM120C	ENST00000375180.7	c.2953G>A	p.Val985Ile	missense_variant	Exon 14 of 16	1	NM_017848.6	ENSP00000364324.2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2953G>A (p.V985I) alteration is located in exon 14 (coding exon 14) of the FAM120C gene. This alteration results from a G to A substitution at nucleotide position 2953, causing the valine (V) at amino acid position 985 to be replaced by an isoleucine (I). 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	0.20
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.69	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.11
Sift	Benign	0.098	T
Sift4G	Pathogenic	0.0	D
Vest4		0.39
MutPred		0.25		Loss of MoRF binding (P = 0.1446);
MVP		0.23
MPC		1.5
ClinPred		0.91	D
GERP RS		4.9
gMVP		0.62

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

Other links and lift over

dbSNP: rs2066763921; hg19: chrX-54107780;