chr7-259915-A-G

Position:

• chr7-259915-A-G

Variant summary

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

The NM_020223.4(FAM20C):​c.1690A>G​(p.Asn564Asp) variant causes a missense change. The variant allele was found at a frequency of 0.458 in 1,534,002 control chromosomes in the GnomAD database, including 164,582 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21013 hom., cov: 35)
  • Exomes 𝑓: 0.45 (143569 hom.)
• Consequence: FAM20C NM_020223.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.01

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 8 pathogenic changes around while only 1 benign (89%) in NM_020223.4
• BP4: Computational evidence support a benign effect (MetaRNN=6.8630966E-6).
• BP6: Variant 7-259915-A-G is Benign according to our data. Variant chr7-259915-A-G is described in ClinVar as [Benign]. Clinvar id is 193731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-259915-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM20C	NM_020223.4	c.1690A>G	p.Asn564Asp	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.1690A>G	p.Asn564Asp	missense_variant	10/10	1	NM_020223.4	ENSP00000322323	P1
FAM20C	ENST00000515795.1	n.1347A>G		non_coding_transcript_exon_variant	7/7	1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78372 AN: 152054 Hom.: 20974 Cov.: 35

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.506

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.498

GnomAD3 exomes AF: 0.436 AC: 61169 AN: 140220 Hom.: 14317 AF XY: 0.437 AC XY: 32948 AN XY: 75324

Gnomad AFR exome AF: 0.672

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.458

Gnomad EAS exome AF: 0.501

Gnomad SAS exome AF: 0.438

Gnomad FIN exome AF: 0.543

Gnomad NFE exome AF: 0.457

Gnomad OTH exome AF: 0.452

GnomAD4 exome AF: 0.452 AC: 624259 AN: 1381830 Hom.: 143569 Cov.: 66 AF XY: 0.451 AC XY: 307215 AN XY: 681428

Gnomad4 AFR exome AF: 0.671

Gnomad4 AMR exome AF: 0.269

Gnomad4 ASJ exome AF: 0.462

Gnomad4 EAS exome AF: 0.475

Gnomad4 SAS exome AF: 0.436

Gnomad4 FIN exome AF: 0.526

Gnomad4 NFE exome AF: 0.448

Gnomad4 OTH exome AF: 0.468

GnomAD4 genome AF: 0.516 AC: 78462 AN: 152172 Hom.: 21013 Cov.: 35 AF XY: 0.516 AC XY: 38407 AN XY: 74382

Gnomad4 AFR AF: 0.667

Gnomad4 AMR AF: 0.371

Gnomad4 ASJ AF: 0.462

Gnomad4 EAS AF: 0.505

Gnomad4 SAS AF: 0.443

Gnomad4 FIN AF: 0.554

Gnomad4 NFE AF: 0.458

Gnomad4 OTH AF: 0.500

Alfa AF: 0.453 Hom.: 11384

Bravo AF: 0.508

TwinsUK AF: 0.439 AC: 1626

ALSPAC AF: 0.430 AC: 1658

ESP6500AA AF: 0.654 AC: 905

ESP6500EA AF: 0.443 AC: 1409

ExAC AF: 0.434 AC: 8679

Asia WGS AF: 0.498 AC: 1729 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Asn564Asp in exon 10 of FAM20C: This variant is not expected to have clinical significance because it has been identified in 72.54% (959/1322) of African chro mosomes by the 1000 Genomes Project (Phase 3; dbSNP rs36139924). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 20, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Lethal osteosclerotic bone dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.28
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.052	T
MetaRNN	Benign	0.0000069	T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.17
Sift	Benign	0.94	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.044
MPC		0.54
ClinPred		0.0017	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.41

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: rs36139924; hg19: chr7-299881; COSMIC: COSV58231921; COSMIC: COSV58231921;