NM_020223.4:c.1690A>G

Variant names:

• chr7-259915-A-G
• rs36139924
• NM_020223.4:c.1690A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N564H) has been classified as Uncertain significance.

• 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
• Publications: 26 publications found

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 Gene-Disease associations (from GenCC):

• lethal osteosclerotic bone dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId is 193731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020223.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM20C	NM_020223.4	MANE Select	c.1690A>G	p.Asn564Asp	missense	Exon 10 of 10	NP_064608.2	Q8IXL6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM20C	ENST00000313766.6	TSL:1 MANE Select	c.1690A>G	p.Asn564Asp	missense	Exon 10 of 10	ENSP00000322323.5	Q8IXL6-1
	FAM20C	ENST00000515795.1	TSL:1	n.1347A>G		non_coding_transcript_exon	Exon 7 of 7
	FAM20C	ENST00000942064.1		c.1951A>G	p.Asn651Asp	missense	Exon 11 of 11	ENSP00000612123.1

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

GnomAD2 exomes AF: 0.436 AC: 61169 AN: 140220 AF XY: 0.437

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 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

African (AFR) AF: 0.671 AC: 21158 AN: 31552

American (AMR) AF: 0.269 AC: 9608 AN: 35654

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 11604 AN: 25138

East Asian (EAS) AF: 0.475 AC: 16945 AN: 35638

South Asian (SAS) AF: 0.436 AC: 34529 AN: 79136

European-Finnish (FIN) AF: 0.526 AC: 17888 AN: 34036

Middle Eastern (MID) AF: 0.486 AC: 2750 AN: 5656

European-Non Finnish (NFE) AF: 0.448 AC: 482762 AN: 1077236

Other (OTH) AF: 0.468 AC: 27015 AN: 57784

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

African (AFR) AF: 0.667 AC: 27694 AN: 41526

American (AMR) AF: 0.371 AC: 5682 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1601 AN: 3468

East Asian (EAS) AF: 0.505 AC: 2606 AN: 5158

South Asian (SAS) AF: 0.443 AC: 2137 AN: 4824

European-Finnish (FIN) AF: 0.554 AC: 5863 AN: 10590

Middle Eastern (MID) AF: 0.582 AC: 170 AN: 292

European-Non Finnish (NFE) AF: 0.458 AC: 31165 AN: 67986

Other (OTH) AF: 0.500 AC: 1056 AN: 2112

Alfa AF: 0.461 Hom.: 20552

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Lethal osteosclerotic bone dysplasia (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.0
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
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

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