7-246502-G-GGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGC

Variant names:

• chr7-246502-G-GGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGC
• rs771282640
• ENST00000515795.1:n.408_409insGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAG

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS1

The ENST00000515795.1(FAM20C):​n.408_409insGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAG variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000589 in 1,358,200 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., cov: 40)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: FAM20C ENST00000515795.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.67
• 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: G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000453 (5/110480) while in subpopulation EAS AF = 0.000923 (4/4334). AF 95% confidence interval is 0.000315. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 40. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM20C	NM_020223.4	c.956+30_956+31insACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCG		intron_variant	Intron 4 of 9	ENST00000313766.6	NP_064608.2
FAM20C	XR_001744837.2	n.1506+30_1506+31insACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCG		intron_variant	Intron 3 of 5
FAM20C	XR_007060116.1	n.1585+30_1585+31insACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCG		intron_variant	Intron 4 of 6
FAM20C	XR_007060117.1	n.1506+30_1506+31insACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCG		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM20C	ENST00000515795.1	n.408_409insGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAG		non_coding_transcript_exon_variant	Exon 1 of 7	1
FAM20C	ENST00000313766.6	c.864-113_864-112insGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAG		intron_variant	Intron 3 of 9	1	NM_020223.4	ENSP00000322323.5

Frequencies

GnomAD3 genomes AF: 0.0000453 AC: 5 AN: 110392 Hom.: 0 Cov.: 40

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000921

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000187

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000240 AC: 3 AN: 1247720 Hom.: 0 Cov.: 34 AF XY: 0.00000323 AC XY: 2 AN XY: 618324

African (AFR) AF: 0.0000386 AC: 1 AN: 25928

American (AMR) AF: 0.0000294 AC: 1 AN: 33988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23084

East Asian (EAS) AF: 0.0000291 AC: 1 AN: 34382

South Asian (SAS) AF: 0.00 AC: 0 AN: 73270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5260

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 965134

Other (OTH) AF: 0.00 AC: 0 AN: 52964

GnomAD4 genome AF: 0.0000453 AC: 5 AN: 110480 Hom.: 0 Cov.: 40 AF XY: 0.0000371 AC XY: 2 AN XY: 53962

African (AFR) AF: 0.00 AC: 0 AN: 23180

American (AMR) AF: 0.00 AC: 0 AN: 12558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2678

East Asian (EAS) AF: 0.000923 AC: 4 AN: 4334

South Asian (SAS) AF: 0.00 AC: 0 AN: 3490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.0000187 AC: 1 AN: 53600

Other (OTH) AF: 0.00 AC: 0 AN: 1574

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=22/178	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs771282640; hg19: chr7-286468;