rs145750007

Positions:

• chr7-259906-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The ENST00000313766.6(FAM20C):​c.1681G>A​(p.Val561Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,535,438 control chromosomes in the GnomAD database, including 254 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V561E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (25 hom., cov: 35)
  • Exomes 𝑓: 0.0046 (229 hom.)
• Consequence: FAM20C ENST00000313766.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.51

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 Benign. Variant got -18 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 4 benign (83%) in ENST00000313766.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035103261).
• BP6: Variant 7-259906-G-A is Benign according to our data. Variant chr7-259906-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 193729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-259906-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM20C	NM_020223.4	c.1681G>A	p.Val561Met	missense_variant	10/10	ENST00000313766.6	NP_064608.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM20C	ENST00000313766.6	c.1681G>A	p.Val561Met	missense_variant	10/10	1	NM_020223.4	ENSP00000322323	P1
FAM20C	ENST00000515795.1	n.1338G>A		non_coding_transcript_exon_variant	7/7	1

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 651 AN: 152244 Hom.: 26 Cov.: 35

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0679

Gnomad SAS AF: 0.0426

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.0117 AC: 1646 AN: 140488 Hom.: 73 AF XY: 0.0134 AC XY: 1014 AN XY: 75466

Gnomad AFR exome AF: 0.000404

Gnomad AMR exome AF: 0.000244

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0654

Gnomad SAS exome AF: 0.0387

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000611

Gnomad OTH exome AF: 0.00764

GnomAD4 exome AF: 0.00459 AC: 6355 AN: 1383076 Hom.: 229 Cov.: 70 AF XY: 0.00556 AC XY: 3797 AN XY: 682332

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.000308

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.0720

Gnomad4 SAS exome AF: 0.0372

Gnomad4 FIN exome AF: 0.0000587

Gnomad4 NFE exome AF: 0.000266

Gnomad4 OTH exome AF: 0.00800

GnomAD4 genome AF: 0.00428 AC: 652 AN: 152362 Hom.: 25 Cov.: 35 AF XY: 0.00533 AC XY: 397 AN XY: 74498

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0673

Gnomad4 SAS AF: 0.0429

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00408 Hom.: 16

Bravo AF: 0.00379

ESP6500AA AF: 0.00145 AC: 2

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.0154 AC: 325

Asia WGS AF: 0.0560 AC: 194 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 21, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 20, 2014

- -

Lethal osteosclerotic bone dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	0.61	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.22
Sift	Benign	0.069	T
Sift4G	Benign	0.087	T
Polyphen		0.61	P
Vest4		0.12
MPC		0.95
ClinPred		0.025	T
GERP RS		-0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.37

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: rs145750007; hg19: chr7-299872; COSMIC: COSV58232068; COSMIC: COSV58232068;