rs148276213

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_020223.4(FAM20C):c.1228T>A(p.Ser410Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00596 in 1,535,878 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 13 hom., cov: 33)

Exomes 𝑓: 0.0060 ( 40 hom. )

Consequence

FAM20C
NM_020223.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:6

Conservation

PhyloP100: 7.07

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]

FAM20C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 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

BP4

Computational evidence support a benign effect (MetaRNN=0.015020758).

BP6

Variant 7-256004-T-A is Benign according to our data. Variant chr7-256004-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 289269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00575 (875/152224) while in subpopulation NFE AF= 0.00653 (444/68010). AF 95% confidence interval is 0.00603. There are 13 homozygotes in gnomad4. There are 489 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM20C	NM_020223.4 linkuse as main transcript	c.1228T>A	p.Ser410Thr	missense_variant	6/10	ENST00000313766.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM20C	ENST00000313766.6 linkuse as main transcript	c.1228T>A	p.Ser410Thr	missense_variant	6/10	1	NM_020223.4	P1	Q8IXL6-1
FAM20C	ENST00000515795.1 linkuse as main transcript	n.885T>A		non_coding_transcript_exon_variant	3/7	1

Frequencies

GnomAD3 genomes

AF:

0.00576

AC:

876

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.0318

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00653

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00481

AC:

674

AN:

140078

Hom.:

AF XY:

0.00492

AC XY:

370

AN XY:

75224

show subpopulations

Gnomad AFR exome

AF:

0.00134

Gnomad AMR exome

AF:

0.000489

Gnomad ASJ exome

AF:

0.00144

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00563

Gnomad FIN exome

AF:

0.0346

Gnomad NFE exome

AF:

0.00560

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.00598

AC:

8275

AN:

1383654

Hom.:

Cov.:

AF XY:

0.00589

AC XY:

4020

AN XY:

682786

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.000701

Gnomad4 ASJ exome

AF:

0.00123

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00490

Gnomad4 FIN exome

AF:

0.0331

Gnomad4 NFE exome

AF:

0.00592

Gnomad4 OTH exome

AF:

0.00492

GnomAD4 genome

AF:

0.00575

AC:

875

AN:

152224

Hom.:

Cov.:

AF XY:

0.00657

AC XY:

489

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.0318

Gnomad4 NFE

AF:

0.00653

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00517

Hom.:

Bravo

AF:

0.00305

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00145

AC:

ESP6500EA

AF:

0.00817

AC:

ExAC

AF:

0.00338

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lethal osteosclerotic bone dysplasia

Pathogenic:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 09, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 0.5092% (rs148276213, 674/140078 alleles, 2 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -
Likely pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jan 17, 2017	The observed mutation is reported in 1000 Genomes and ExAC databases. The in silico prediction of the mutation is damaging by MutationTaster2 and PROVEAN. The given mutation is probably damaging by Polyphen2 and it is benign by SIFT. The dbSNP reference number of the given mutation is rs148276213. The proband, born of a third degree consanguinity, presented with facial dysmorphism, mild hypotonia and microcephaly. Her CT-scan report showed mild cortical atrophy. Her EEG and karyotype were normal. She was found normal for William syndrome. Her array CGH report showed no quantitative genomic imbalance. She was observed to have chronic constipation, hyperactive behavior, two episodes of seizures, delay in speech, delay in cognitive and motor milestones. Her MRI report showed corpus callosal dysgenesis with absent rostral area. She was also detected with intrauterine growth restriction (IUGR). She was born through Lower segment Cesarian section (LSCS). She presented no neonatal difficulties. Her parents were found to be heterozygous for this allele. -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	FAM20C: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 30, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.015

MetaSVM

Uncertain

-0.19

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.57

Sift

Benign

0.31

Sift4G

Benign

0.23

Polyphen

0.97

Vest4

0.69

MVP

0.79

MPC

1.2

ClinPred

0.014

GERP RS

4.9

Varity_R

0.42

gMVP

0.89

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over