7-193245-G-T

Variant names:

• chr7-193245-G-T
• rs150401144
• NM_020223.4:c.46G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020223.4(FAM20C):​c.46G>T​(p.Val16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,466,390 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (26 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (20 hom.)
• Consequence: FAM20C NM_020223.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.00
• Publications: 3 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

ENSG00000240093 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.003346026).
• BP6: Variant 7-193245-G-T is Benign according to our data. Variant chr7-193245-G-T is described in ClinVar as Benign. ClinVar VariationId is 193426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0111 (1670/150092) while in subpopulation AFR AF = 0.0385 (1593/41344). AF 95% confidence interval is 0.037. There are 26 homozygotes in GnomAd4. There are 768 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 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.46G>T	p.Val16Leu	missense	Exon 1 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.46G>T	p.Val16Leu	missense	Exon 1 of 10	ENSP00000322323.5	Q8IXL6-1
	FAM20C	ENST00000942064.1		c.46G>T	p.Val16Leu	missense	Exon 1 of 11	ENSP00000612123.1
	FAM20C	ENST00000866115.1		c.46G>T	p.Val16Leu	missense	Exon 1 of 11	ENSP00000536174.1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1672 AN: 149984 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00318

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000178

Gnomad OTH AF: 0.00776

GnomAD2 exomes AF: 0.00148 AC: 172 AN: 116294 AF XY: 0.00112

Gnomad AFR exome AF: 0.0368

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000656

Gnomad OTH exome AF: 0.000868

GnomAD4 exome AF: 0.000943 AC: 1241 AN: 1316298 Hom.: 20 Cov.: 30 AF XY: 0.000808 AC XY: 525 AN XY: 649842

African (AFR) AF: 0.0394 AC: 1048 AN: 26580

American (AMR) AF: 0.00143 AC: 46 AN: 32230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22214

East Asian (EAS) AF: 0.00 AC: 0 AN: 29504

South Asian (SAS) AF: 0.0000781 AC: 6 AN: 76776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32294

Middle Eastern (MID) AF: 0.000567 AC: 3 AN: 5288

European-Non Finnish (NFE) AF: 0.0000250 AC: 26 AN: 1038096

Other (OTH) AF: 0.00210 AC: 112 AN: 53316

GnomAD4 genome AF: 0.0111 AC: 1670 AN: 150092 Hom.: 26 Cov.: 33 AF XY: 0.0105 AC XY: 768 AN XY: 73292

African (AFR) AF: 0.0385 AC: 1593 AN: 41344

American (AMR) AF: 0.00318 AC: 48 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000179 AC: 12 AN: 67218

Other (OTH) AF: 0.00768 AC: 16 AN: 2084

Alfa AF: 0.00234 Hom.: 4

ESP6500AA AF: 0.0332 AC: 93

ESP6500EA AF: 0.000191 AC: 1

ExAC AF: 0.00340 AC: 74

Asia WGS AF: 0.00250 AC: 8 AN: 3212

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.62	T
PhyloP100		3.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.19
Sift	Benign	0.16	T
Sift4G	Benign	0.22	T
Polyphen		0.0020	B
Vest4		0.17
MutPred		0.35		Loss of MoRF binding (P = 0.0982)
MVP		0.37
MPC		0.47
ClinPred		0.0071	T
GERP RS		2.9
Varity_R		0.16
gMVP		0.66
Mutation Taster		=89/11	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: rs150401144; hg19: chr7-193245;