chr11-59149222-G-A

Position:

• chr11-59149222-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001312909.2(FAM111A):​c.81+269G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 334,512 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (41 hom., cov: 32)
  • Exomes 𝑓: 0.025 (74 hom.)
• Consequence: FAM111A NM_001312909.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.443

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 11-59149222-G-A is Benign according to our data. Variant chr11-59149222-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1208397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0192 (2912/152056) while in subpopulation SAS AF= 0.0367 (177/4828). AF 95% confidence interval is 0.0322. There are 41 homozygotes in gnomad4. There are 1371 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2912 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM111A	NM_001312909.2	c.81+269G>A		intron_variant		ENST00000675163.1	NP_001299838.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM111A	ENST00000675163.1	c.81+269G>A		intron_variant			NM_001312909.2	ENSP00000501952.1

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2912 AN: 151938 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.00474

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0254

GnomAD4 exome AF: 0.0249 AC: 4535 AN: 182456 Hom.: 74 Cov.: 0 AF XY: 0.0247 AC XY: 2386 AN XY: 96444

Gnomad4 AFR exome AF: 0.00316

Gnomad4 AMR exome AF: 0.0137

Gnomad4 ASJ exome AF: 0.0344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0345

Gnomad4 FIN exome AF: 0.0172

Gnomad4 NFE exome AF: 0.0282

Gnomad4 OTH exome AF: 0.0228

GnomAD4 genome AF: 0.0192 AC: 2912 AN: 152056 Hom.: 41 Cov.: 32 AF XY: 0.0184 AC XY: 1371 AN XY: 74348

Gnomad4 AFR AF: 0.00473

Gnomad4 AMR AF: 0.0179

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0367

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.0284

Gnomad4 OTH AF: 0.0252

Alfa AF: 0.0149 Hom.: 6

Bravo AF: 0.0181

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.15
DANN	Benign	0.37

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: rs79009474; hg19: chr11-58916695;