rs796051849

Positions:

• chr7-255939-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_020223.4(FAM20C):​c.1163T>G​(p.Leu388Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAM20C NM_020223.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.07

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest Kinase domain (size 211) in uniprot entity FA20C_HUMAN there are 18 pathogenic changes around while only 4 benign (82%) in NM_020223.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 7-255939-T-G is Pathogenic according to our data. Variant chr7-255939-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 1024.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-255939-T-G is described in UniProt as null. Variant chr7-255939-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM20C	NM_020223.4	c.1163T>G	p.Leu388Arg	missense_variant	6/10	ENST00000313766.6
FAM20C	XR_007060117.1	n.1713T>G		non_coding_transcript_exon_variant	5/5
FAM20C	XR_001744837.2			downstream_gene_variant
FAM20C	XR_007060116.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM20C	ENST00000313766.6	c.1163T>G	p.Leu388Arg	missense_variant	6/10	1	NM_020223.4	P1
FAM20C	ENST00000515795.1	n.820T>G		non_coding_transcript_exon_variant	3/7	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lethal osteosclerotic bone dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.58	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.93		Loss of helix (P = 0.0626);
MVP		0.95
MPC		1.7
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.99

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

Other links and lift over

dbSNP: rs796051849; hg19: chr7-295905;