rs587777012

Positions:

• chr11-59153199-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001312909.2(FAM111A):​c.1531T>C​(p.Tyr511His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM111A NM_001312909.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: -0.0890

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM111A	NM_001312909.2	c.1531T>C	p.Tyr511His	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.1531T>C	p.Tyr511His	missense_variant	6/6		NM_001312909.2	ENSP00000501952.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant Kenny-Caffey syndrome Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 06, 2013	- -
Uncertain significance, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Jun 27, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	9.7
DANN	Benign	0.63
DEOGEN2	Uncertain	0.52	D;D;D;D;D
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.38	.;T;.;.;.
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.7	L;L;L;L;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.0	N;N;N;N;N
REVEL	Benign	0.093
Sift	Benign	0.15	T;T;T;T;T
Sift4G	Benign	0.090	T;T;T;T;T
Polyphen		0.13	B;B;B;B;B
Vest4		0.75
MutPred		0.32		Loss of phosphorylation at Y511 (P = 0.0075);Loss of phosphorylation at Y511 (P = 0.0075);Loss of phosphorylation at Y511 (P = 0.0075);Loss of phosphorylation at Y511 (P = 0.0075);Loss of phosphorylation at Y511 (P = 0.0075);
MVP		0.58
MPC		0.034
ClinPred		0.055	T
GERP RS		2.7
Varity_R		0.039
gMVP		0.56

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: rs587777012; hg19: chr11-58920672;