7-256004-T-C

Variant names:

• chr7-256004-T-C
• rs148276213
• NM_020223.4:c.1228T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_020223.4(FAM20C):​c.1228T>C​(p.Ser410Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAM20C NM_020223.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 8 ACMG points.

• PM1: In a region_of_interest Kinase domain (size 211) in uniprot entity FA20C_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_020223.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM20C	NM_020223.4	c.1228T>C	p.Ser410Pro	missense_variant	Exon 6 of 10	ENST00000313766.6	NP_064608.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM20C	ENST00000313766.6	c.1228T>C	p.Ser410Pro	missense_variant	Exon 6 of 10	1	NM_020223.4	ENSP00000322323.5
FAM20C	ENST00000515795.1	n.885T>C		non_coding_transcript_exon_variant	Exon 3 of 7	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.69	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.70		Loss of phosphorylation at S410 (P = 0.0206);
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.88
gMVP		0.97

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: rs148276213; hg19: chr7-295970;