dbSNP rs587777015: FAM111A:p.Pro527Thr (chr11-59153247-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_001312909.2(FAM111A):c.1579C>A(p.Pro527Thr) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P527A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

FAM111A
NM_001312909.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: -1.01

Publications

5 publications found

Variant links:

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 links:

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

FAM111A-DT links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-59153247-C-A is Pathogenic according to our data. Variant chr11-59153247-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 56815.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.18154195). . Strength limited to SUPPORTING due to the PP5.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM111A	NM_001312909.2	MANE Select	c.1579C>A	p.Pro527Thr	missense	Exon 6 of 6	NP_001299838.1	Q96PZ2
FAM111A	NM_001142519.3		c.1579C>A	p.Pro527Thr	missense	Exon 5 of 5	NP_001135991.1	Q96PZ2
FAM111A	NM_001142520.3		c.1579C>A	p.Pro527Thr	missense	Exon 5 of 5	NP_001135992.1	Q96PZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM111A	ENST00000675163.1	MANE Select	c.1579C>A	p.Pro527Thr	missense	Exon 6 of 6	ENSP00000501952.1	Q96PZ2
FAM111A	ENST00000531147.1	TSL:1	c.1579C>A	p.Pro527Thr	missense	Exon 2 of 2	ENSP00000431631.1	Q96PZ2
FAM111A	ENST00000361723.7	TSL:2	c.1579C>A	p.Pro527Thr	missense	Exon 4 of 4	ENSP00000355264.3	Q96PZ2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Osteocraniostenosis (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.44

(source)

DANN

Benign

0.34

DEOGEN2

Benign

0.41

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.49

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

-1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.0

REVEL

Benign

0.033

Sift

Benign

0.60

Sift4G

Benign

0.97

Polyphen

0.67

Vest4

0.092

MutPred

0.27

Gain of helix (P = 0.062)

MVP

0.41

MPC

0.11

ClinPred

0.27

GERP RS

-2.6

Varity_R

0.046

gMVP

0.61

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over