chr7-256004-T-A

Position:

• chr7-256004-T-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020223.4(FAM20C):​c.1228T>A​(p.Ser410Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00596 in 1,535,878 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (40 hom.)
• Consequence: FAM20C NM_020223.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: 7.07

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a region_of_interest Kinase domain (size 211) in uniprot entity FA20C_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_020223.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.015020758).
• BP6: Variant 7-256004-T-A is Benign according to our data. Variant chr7-256004-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 289269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00575 (875/152224) while in subpopulation NFE AF= 0.00653 (444/68010). AF 95% confidence interval is 0.00603. There are 13 homozygotes in gnomad4. There are 489 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM20C	NM_020223.4	c.1228T>A	p.Ser410Thr	missense_variant	6/10	ENST00000313766.6	NP_064608.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM20C	ENST00000313766.6	c.1228T>A	p.Ser410Thr	missense_variant	6/10	1	NM_020223.4	ENSP00000322323	P1
FAM20C	ENST00000515795.1	n.885T>A		non_coding_transcript_exon_variant	3/7	1

Frequencies

GnomAD3 genomes AF: 0.00576 AC: 876 AN: 152106 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0318

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00653

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00481 AC: 674 AN: 140078 Hom.: 2 AF XY: 0.00492 AC XY: 370 AN XY: 75224

Gnomad AFR exome AF: 0.00134

Gnomad AMR exome AF: 0.000489

Gnomad ASJ exome AF: 0.00144

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00563

Gnomad FIN exome AF: 0.0346

Gnomad NFE exome AF: 0.00560

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00598 AC: 8275 AN: 1383654 Hom.: 40 Cov.: 32 AF XY: 0.00589 AC XY: 4020 AN XY: 682786

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.000701

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00490

Gnomad4 FIN exome AF: 0.0331

Gnomad4 NFE exome AF: 0.00592

Gnomad4 OTH exome AF: 0.00492

GnomAD4 genome AF: 0.00575 AC: 875 AN: 152224 Hom.: 13 Cov.: 33 AF XY: 0.00657 AC XY: 489 AN XY: 74428

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0318

Gnomad4 NFE AF: 0.00653

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00517 Hom.: 1

Bravo AF: 0.00305

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00145 AC: 2

ESP6500EA AF: 0.00817 AC: 26

ExAC AF: 0.00338 AC: 83

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lethal osteosclerotic bone dysplasia Pathogenic:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 09, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 0.5092% (rs148276213, 674/140078 alleles, 2 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -
Likely pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jan 17, 2017	The observed mutation is reported in 1000 Genomes and ExAC databases. The in silico prediction of the mutation is damaging by MutationTaster2 and PROVEAN. The given mutation is probably damaging by Polyphen2 and it is benign by SIFT. The dbSNP reference number of the given mutation is rs148276213. The proband, born of a third degree consanguinity, presented with facial dysmorphism, mild hypotonia and microcephaly. Her CT-scan report showed mild cortical atrophy. Her EEG and karyotype were normal. She was found normal for William syndrome. Her array CGH report showed no quantitative genomic imbalance. She was observed to have chronic constipation, hyperactive behavior, two episodes of seizures, delay in speech, delay in cognitive and motor milestones. Her MRI report showed corpus callosal dysgenesis with absent rostral area. She was also detected with intrauterine growth restriction (IUGR). She was born through Lower segment Cesarian section (LSCS). She presented no neonatal difficulties. Her parents were found to be heterozygous for this allele. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	FAM20C: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 30, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	-0.19	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.57
Sift	Benign	0.31	T
Sift4G	Benign	0.23	T
Polyphen		0.97	D
Vest4		0.69
MVP		0.79
MPC		1.2
ClinPred		0.014	T
GERP RS		4.9
Varity_R		0.42
gMVP		0.89

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: rs148276213; hg19: chr7-295970;