rs587777011

Positions:

• chr11-59153374-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_001312909.2(FAM111A):​c.1706G>A​(p.Arg569His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM111A NM_001312909.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:2 O:1
• Conservation: PhyloP100: -1.51

Genes affected

FAM111A (HGNC:24725): (FAM111 trypsin like peptidase A) The protein encoded by this gene is cell-cycle regulated, and has nuclear localization. The C-terminal half of the protein shares homology with trypsin-like peptidases and it contains a PCNA-interacting peptide (PIP) box, that is necessary for its co-localization with proliferating cell nuclear antigen (PCNA). Reduced expression of this gene resulted in DNA replication defects, consistent with the demonstrated role for this gene in Simian Virus 40 (SV40) viral replication. Mutations in this gene have been associated with Kenny-Caffey syndrome (KCS) type 2 and the more severe osteocraniostenosis (OCS, also known as Gracile Bone Dysplasia), both characterized by short stature, hypoparathyroidism, bone development abnormalities, and hypocalcemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-59153374-G-A is Pathogenic according to our data. Variant chr11-59153374-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24506095). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM111A	NM_001312909.2	c.1706G>A	p.Arg569His	missense_variant	6/6	ENST00000675163.1	NP_001299838.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM111A	ENST00000675163.1	c.1706G>A	p.Arg569His	missense_variant	6/6		NM_001312909.2	ENSP00000501952.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Kenny-Caffey syndrome Pathogenic:4 Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Jun 27, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2014	- -
Pathogenic, no assertion criteria provided	research	Clinical Genetics Laboratory, Federal University of Health Sciences of Porto Alegre	May 22, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, loss of function is an unlikely mechanism. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (16 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and observed multiple times as de novo in individuals with Kenny-Caffey syndrome or nanophthalmos (ClinVar, DECIPHER, PMID: 32996714; PMID: 23684011). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, no assertion criteria provided	research	Institute of Medical Molecular Genetics, University of Zurich	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000056810). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 07, 2022	ClinVar contains an entry for this variant (Variation ID: 56810). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This missense change has been observed in individual(s) with Kenny-Caffey syndrome (PMID: 23684011, 23996431, 24635597, 24970356). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 569 of the FAM111A protein (p.Arg569His). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2022	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28138333, 32765931, 24970356, 23996431, 24635597, 32996714, 33010201, 33258288, 23684011) -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2018

- -

Osteocraniostenosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Osteocraniostenosis;C4316787:Autosomal dominant Kenny-Caffey syndrome Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as Pathogenic and reported on 03-20-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.1
DANN	Benign	0.42
DEOGEN2	Benign	0.0081	T;T;T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.47	.;T;.;.;.
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L;L;L;L;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.0	N;N;N;N;N
REVEL	Benign	0.031
Sift	Benign	0.54	T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;T
Polyphen		0.90	P;P;P;P;P
Vest4		0.64
MutPred		0.29		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.29
MPC		0.022
ClinPred		0.11	T
GERP RS		-7.0
Varity_R		0.046
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: rs587777011; hg19: chr11-58920847;