chr11-59148953-G-C

Variant names:

• chr11-59148953-G-C
• rs747211416
• NM_001312909.2:c.81G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001312909.2(FAM111A):​c.81G>C​(p.Pro27Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P27P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FAM111A NM_001312909.2 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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.81G>C	p.Pro27Pro	splice_region synonymous	Exon 5 of 6	NP_001299838.1	Q96PZ2
	FAM111A	NM_001142519.3		c.81G>C	p.Pro27Pro	splice_region synonymous	Exon 4 of 5	NP_001135991.1	Q96PZ2
	FAM111A	NM_001142520.3		c.81G>C	p.Pro27Pro	splice_region synonymous	Exon 4 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.81G>C	p.Pro27Pro	splice_region synonymous	Exon 5 of 6	ENSP00000501952.1	Q96PZ2
	FAM111A	ENST00000531147.1	TSL:1	c.81G>C	p.Pro27Pro	splice_region synonymous	Exon 1 of 2	ENSP00000431631.1	Q96PZ2
	FAM111A	ENST00000361723.7	TSL:2	c.81G>C	p.Pro27Pro	splice_region synonymous	Exon 3 of 4	ENSP00000355264.3	Q96PZ2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453568 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 723602

⚠️ 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: 33292

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 85994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104732

Other (OTH) AF: 0.00 AC: 0 AN: 60072

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.61
PhyloP100		1.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.44		Position offset: 0

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

Other links and lift over

dbSNP: rs747211416; hg19: chr11-58916426;