7-193254-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_020223.4(FAM20C):c.55G>T(p.Val19Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,466,828 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V19V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: FAM20C NM_020223.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.164

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018017918).
• BP6: Variant 7-193254-G-T is Benign according to our data. Variant chr7-193254-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1517259.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr7-193254-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00066 (99/150080) while in subpopulation AFR AF= 0.00223 (92/41308). AF 95% confidence interval is 0.00186. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM20C	NM_020223.4	c.55G>T	p.Val19Leu	missense_variant	1/10	ENST00000313766.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM20C	ENST00000313766.6	c.55G>T	p.Val19Leu	missense_variant	1/10	1	NM_020223.4	P1
	ENST00000467050.1	n.233+694C>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000660 AC: 99 AN: 149972 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000265

Gnomad ASJ AF: 0.000581

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.000114 AC: 13 AN: 113552 Hom.: 0 AF XY: 0.000112 AC XY: 7 AN XY: 62326

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.000186

Gnomad ASJ exome AF: 0.000263

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000890

GnomAD4 exome AF: 0.000109 AC: 144 AN: 1316748 Hom.: 0 Cov.: 30 AF XY: 0.000111 AC XY: 72 AN XY: 650060

Gnomad4 AFR exome AF: 0.00189

Gnomad4 AMR exome AF: 0.000249

Gnomad4 ASJ exome AF: 0.000585

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000520

Gnomad4 OTH exome AF: 0.000299

GnomAD4 genome AF: 0.000660 AC: 99 AN: 150080 Hom.: 0 Cov.: 33 AF XY: 0.000628 AC XY: 46 AN XY: 73276

Gnomad4 AFR AF: 0.00223

Gnomad4 AMR AF: 0.000265

Gnomad4 ASJ AF: 0.000581

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000392 Hom.: 0

Bravo AF: 0.000812

ExAC AF: 0.000231 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.55G>T (p.V19L) alteration is located in exon 1 (coding exon 1) of the FAM20C gene. This alteration results from a G to T substitution at nucleotide position 55, causing the valine (V) at amino acid position 19 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	15
Dann	Benign	0.93
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.25
Sift	Benign	0.73	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.051
MutPred		0.37		Loss of catalytic residue at V19 (P = 0.0045);
MVP		0.23
MPC		0.47
ClinPred		0.0075	T
GERP RS		0.29
Varity_R		0.051
gMVP		0.49

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: rs529612835; hg19: chr7-193254;