rs587777012

Variant names:

• chr11-59153199-T-C
• rs587777012
• NM_001312909.2:c.1531T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

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. 14/22 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
• Publications: 11 publications found

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]

FAM111A-DT (HGNC:53752): (FAM111A divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-59153199-T-C is Pathogenic according to our data. Variant chr11-59153199-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 56812.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001312909.2. 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
	FAM111A	NM_001312909.2	MANE Select	c.1531T>C	p.Tyr511His	missense	Exon 6 of 6	NP_001299838.1	Q96PZ2
	FAM111A	NM_001142519.3		c.1531T>C	p.Tyr511His	missense	Exon 5 of 5	NP_001135991.1	Q96PZ2
	FAM111A	NM_001142520.3		c.1531T>C	p.Tyr511His	missense	Exon 5 of 5	NP_001135992.1	Q96PZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM111A	ENST00000675163.1	MANE Select	c.1531T>C	p.Tyr511His	missense	Exon 6 of 6	ENSP00000501952.1	Q96PZ2
	FAM111A	ENST00000531147.1	TSL:1	c.1531T>C	p.Tyr511His	missense	Exon 2 of 2	ENSP00000431631.1	Q96PZ2
	FAM111A	ENST00000361723.7	TSL:2	c.1531T>C	p.Tyr511His	missense	Exon 4 of 4	ENSP00000355264.3	Q96PZ2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	1	-	Autosomal dominant Kenny-Caffey syndrome (2)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.089
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.093
Sift	Benign	0.15	T
Sift4G	Benign	0.090	T
Polyphen		0.13	B
Vest4		0.75
MutPred		0.32		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
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs587777012; hg19: chr11-58920672;