NM_178468.6:c.1612G>C

Variant names:

• chr20-35287167-C-G
• rs200282148
• NM_178468.6:c.1612G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178468.6(FAM83C):​c.1612G>C​(p.Glu538Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E538K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FAM83C NM_178468.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0660
• Publications: 0 publications found

Genes affected

FAM83C (HGNC:16121): (family with sequence similarity 83 member C) This gene encodes a member of the family with sequence similarity 83 protein family. The encoded protein may be involved in regulating MAPK signaling in cancer cells. [provided by RefSeq, Mar 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0567151).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178468.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM83C	NM_178468.6	MANE Select	c.1612G>C	p.Glu538Gln	missense	Exon 4 of 4	NP_848563.1	Q9BQN1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM83C	ENST00000374408.4	TSL:1 MANE Select	c.1612G>C	p.Glu538Gln	missense	Exon 4 of 4	ENSP00000363529.3	Q9BQN1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454482 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 723810

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111312

Other (OTH) AF: 0.00 AC: 0 AN: 60270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.4
DANN	Benign	0.90
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.066
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.027
Sift	Benign	0.20	T
Sift4G	Benign	0.17	T
Polyphen		0.0060	B
Vest4		0.12
MutPred		0.087		Loss of methylation at R535 (P = 0.098)
MVP		0.11
MPC		0.19
ClinPred		0.079	T
GERP RS		3.2
Varity_R		0.059
gMVP		0.066
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs200282148; hg19: chr20-33874970;