chr7-193230-G-C

Variant names:

• chr7-193230-G-C
• rs1367064980
• NM_020223.4:c.31G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020223.4(FAM20C):​c.31G>C​(p.Val11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,464,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. V11M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: FAM20C NM_020223.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.71
• Publications: 0 publications found

Genes affected

FAM20C (HGNC:22140): (FAM20C golgi associated secretory pathway kinase) This gene encodes a member of the family of secreted protein kinases. The encoded protein binds calcium and phosphorylates proteins involved in bone mineralization. Mutations in this gene are associated with the autosomal recessive disorder Raine syndrome. [provided by RefSeq, Apr 2014]

FAM20C Gene-Disease associations (from GenCC):

• lethal osteosclerotic bone dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ENSG00000240093 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38200146).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020223.4. 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
	FAM20C	NM_020223.4	MANE Select	c.31G>C	p.Val11Leu	missense	Exon 1 of 10	NP_064608.2	Q8IXL6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM20C	ENST00000313766.6	TSL:1 MANE Select	c.31G>C	p.Val11Leu	missense	Exon 1 of 10	ENSP00000322323.5	Q8IXL6-1
	FAM20C	ENST00000942064.1		c.31G>C	p.Val11Leu	missense	Exon 1 of 11	ENSP00000612123.1
	FAM20C	ENST00000866115.1		c.31G>C	p.Val11Leu	missense	Exon 1 of 11	ENSP00000536174.1

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149834 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.61e-7 AC: 1 AN: 1314634 Hom.: 0 Cov.: 30 AF XY: 0.00000154 AC XY: 1 AN XY: 649296

African (AFR) AF: 0.00 AC: 0 AN: 26690

American (AMR) AF: 0.00 AC: 0 AN: 32436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22090

East Asian (EAS) AF: 0.0000338 AC: 1 AN: 29552

South Asian (SAS) AF: 0.00 AC: 0 AN: 76992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5224

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1036500

Other (OTH) AF: 0.00 AC: 0 AN: 53048

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149834 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 73088

African (AFR) AF: 0.00 AC: 0 AN: 41178

American (AMR) AF: 0.00 AC: 0 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67176

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0059	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.22	D
PhyloP100		2.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.012	D
Sift4G	Benign	0.31	T
Polyphen		0.59	P
Vest4		0.23
MutPred		0.63		Loss of catalytic residue at V11 (P = 0.0419)
MVP		0.73
MPC		1.2
ClinPred		0.84	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.25
gMVP		0.63
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs1367064980; hg19: chr7-193230;