rs797044462

chr7-248340-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_020223.4(FAM20C):c.982C>T(p.Pro328Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000722 in 1,384,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. P328P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: FAM20C NM_020223.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.54

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant 7-248340-C-T is Pathogenic according to our data. Variant chr7-248340-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30878.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-248340-C-T is described in UniProt as null. Variant chr7-248340-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM20C	NM_020223.4	c.982C>T	p.Pro328Ser	missense_variant	5/10	ENST00000313766.6
FAM20C	XR_001744837.2	n.1532C>T		non_coding_transcript_exon_variant	4/6
FAM20C	XR_007060116.1	n.1611C>T		non_coding_transcript_exon_variant	5/7
FAM20C	XR_007060117.1	n.1532C>T		non_coding_transcript_exon_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM20C	ENST00000313766.6	c.982C>T	p.Pro328Ser	missense_variant	5/10	1	NM_020223.4	P1
FAM20C	ENST00000515795.1	n.639C>T		non_coding_transcript_exon_variant	2/7	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000705 AC: 1 AN: 141828 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 75838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000941

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384732 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 683304

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Aug 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.87	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.051	T
Polyphen		1.0	D
Vest4		0.86
MutPred		0.57		Gain of MoRF binding (P = 0.0276);
MVP		0.98
MPC		1.2
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.65
gMVP		0.92

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: rs797044462; hg19: chr7-288306;