rs144007479

Variant names:

• chr7-255994-T-A
• rs144007479
• NM_020223.4:c.1218T>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020223.4(FAM20C):​c.1218T>A​(p.Pro406Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,536,036 control chromosomes in the GnomAD database, including 730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (64 hom., cov: 33)
  • Exomes 𝑓: 0.028 (666 hom.)
• Consequence: FAM20C NM_020223.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.50
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 7-255994-T-A is Benign according to our data. Variant chr7-255994-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 504906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0262 (3989/152290) while in subpopulation NFE AF = 0.0315 (2142/68012). AF 95% confidence interval is 0.0304. There are 64 homozygotes in GnomAd4. There are 1841 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 64 AR gene

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.1218T>A	p.Pro406Pro	synonymous	Exon 6 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.1218T>A	p.Pro406Pro	synonymous	Exon 6 of 10	ENSP00000322323.5	Q8IXL6-1
	FAM20C	ENST00000515795.1	TSL:1	n.875T>A		non_coding_transcript_exon	Exon 3 of 7
	FAM20C	ENST00000942064.1		c.1479T>A	p.Pro493Pro	synonymous	Exon 7 of 11	ENSP00000612123.1

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3993 AN: 152172 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0225 AC: 3159 AN: 140380 AF XY: 0.0218

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.0151

Gnomad ASJ exome AF: 0.0341

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.0330

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0285 AC: 39386 AN: 1383746 Hom.: 666 Cov.: 32 AF XY: 0.0279 AC XY: 19059 AN XY: 682822

African (AFR) AF: 0.0299 AC: 945 AN: 31590

American (AMR) AF: 0.0163 AC: 581 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.0345 AC: 868 AN: 25152

East Asian (EAS) AF: 0.000112 AC: 4 AN: 35728

South Asian (SAS) AF: 0.00817 AC: 647 AN: 79230

European-Finnish (FIN) AF: 0.0171 AC: 583 AN: 34018

Middle Eastern (MID) AF: 0.0380 AC: 216 AN: 5686

European-Non Finnish (NFE) AF: 0.0316 AC: 34053 AN: 1078760

Other (OTH) AF: 0.0257 AC: 1489 AN: 57894

GnomAD4 genome AF: 0.0262 AC: 3989 AN: 152290 Hom.: 64 Cov.: 33 AF XY: 0.0247 AC XY: 1841 AN XY: 74470

African (AFR) AF: 0.0284 AC: 1182 AN: 41566

American (AMR) AF: 0.0170 AC: 260 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4824

European-Finnish (FIN) AF: 0.0195 AC: 207 AN: 10616

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0315 AC: 2142 AN: 68012

Other (OTH) AF: 0.0175 AC: 37 AN: 2110

Alfa AF: 0.0297 Hom.: 15

Bravo AF: 0.0269

Asia WGS AF: 0.00895 AC: 32 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.0
DANN	Benign	0.67
PhyloP100		-1.5
Mutation Taster		=99/1	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: rs144007479; hg19: chr7-295960;