NM_001312909.2:c.82-1G>C

Variant names:

• chr11-59151749-G-C
• rs1590950663
• NM_001312909.2:c.82-1G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001312909.2(FAM111A):​c.82-1G>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,412,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM111A NM_001312909.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51
• Publications: 0 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 2 ACMG points.

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

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.82-1G>C		splice_acceptor intron	N/A	NP_001299838.1	Q96PZ2
	FAM111A	NM_001142519.3		c.82-1G>C		splice_acceptor intron	N/A	NP_001135991.1	Q96PZ2
	FAM111A	NM_001142520.3		c.82-1G>C		splice_acceptor intron	N/A	NP_001135992.1	Q96PZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM111A	ENST00000675163.1	MANE Select	c.82-1G>C		splice_acceptor intron	N/A	ENSP00000501952.1	Q96PZ2
	FAM111A	ENST00000531147.1	TSL:1	c.82-1G>C		splice_acceptor intron	N/A	ENSP00000431631.1	Q96PZ2
	FAM111A	ENST00000361723.7	TSL:2	c.82-1G>C		splice_acceptor intron	N/A	ENSP00000355264.3	Q96PZ2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1412622 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 701224

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30726

American (AMR) AF: 0.00 AC: 0 AN: 31920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23256

East Asian (EAS) AF: 0.00 AC: 0 AN: 39366

South Asian (SAS) AF: 0.00 AC: 0 AN: 78488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5512

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1093260

Other (OTH) AF: 0.00 AC: 0 AN: 58106

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Pathogenic	26
DANN	Benign	0.85
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.57	D
PhyloP100		1.5
GERP RS		3.9
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 11
DS_AL_spliceai		0.69		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1590950663; hg19: chr11-58919222;