7-256001-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_020223.4(FAM20C):​c.1225C>T​(p.Arg409Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000065 in 1,383,674 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R409H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000065 ( 0 hom. )

Consequence

FAM20C
NM_020223.4 missense

Scores

14
3
1

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.05
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a region_of_interest Kinase domain (size 211) in uniprot entity FA20C_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_020223.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-256002-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3053978.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 7-256001-C-T is Pathogenic according to our data. Variant chr7-256001-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183311.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-256001-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FAM20CNM_020223.4 linkc.1225C>T p.Arg409Cys missense_variant Exon 6 of 10 ENST00000313766.6 NP_064608.2 Q8IXL6-1
FAM20CXR_001744837.2 linkn.*66C>T downstream_gene_variant
FAM20CXR_007060116.1 linkn.*66C>T downstream_gene_variant
FAM20CXR_007060117.1 linkn.*52C>T downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FAM20CENST00000313766.6 linkc.1225C>T p.Arg409Cys missense_variant Exon 6 of 10 1 NM_020223.4 ENSP00000322323.5 Q8IXL6-1
FAM20CENST00000515795.1 linkn.882C>T non_coding_transcript_exon_variant Exon 3 of 7 1
FAM20CENST00000512382.1 linkn.-194C>T upstream_gene_variant 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000714
AC:
1
AN:
140084
Hom.:
0
AF XY:
0.0000133
AC XY:
1
AN XY:
75242
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000440
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000650
AC:
9
AN:
1383674
Hom.:
0
Cov.:
32
AF XY:
0.00000586
AC XY:
4
AN XY:
682792
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000884
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000185
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.0000411
AC:
1

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Neonatal death;C0424503:Abnormal facial shape;C0431380:Cortical dysplasia;CN228280:Severe brain malformation Pathogenic:1
Dec 01, 2014
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.70
D
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.62
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.73
D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-7.3
D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.83
Loss of disorder (P = 0.0262);
MVP
0.93
MPC
1.6
ClinPred
0.97
D
GERP RS
4.9
Varity_R
0.76
gMVP
0.96

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs730882220; hg19: chr7-295967; COSMIC: COSV58237435; COSMIC: COSV58237435; API