11-59124903-C-CA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PVS1_Strong BP6_Moderate BS2

The NM_198947.4(FAM111B):c.816dup(p.Ala273SerfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,416,642 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: FAM111B NM_198947.4 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.42

Genes affected

FAM111B (HGNC:24200): (FAM111 trypsin like peptidase B) This gene encodes a protein with a trypsin-like cysteine/serine peptidase domain in the C-terminus. Mutations in this gene are associated with an autosomal dominant form of hereditary fibrosing poikiloderma (HFP). Affected individuals display mottled pigmentation, telangiectasia, epidermal atrophy, tendon contractures, and progressive pulmonary fibrosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. A paralog of this gene which also has a trypsin‐like peptidase domain, FAM111A, is located only 16 kb from this gene on human chromosome 11q12.1. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• BP6: Variant 11-59124903-C-CA is Benign according to our data. Variant chr11-59124903-C-CA is described in ClinVar as [Benign]. Clinvar id is 3060639.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 213 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM111B	NM_198947.4	c.816dup	p.Ala273SerfsTer9	frameshift_variant	4/4	ENST00000343597.4
FAM111B	NM_001142703.2	c.726dup	p.Ala243SerfsTer9	frameshift_variant	3/3
FAM111B	NM_001142704.2	c.726dup	p.Ala243SerfsTer9	frameshift_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM111B	ENST00000343597.4	c.816dup	p.Ala273SerfsTer9	frameshift_variant	4/4	1	NM_198947.4	P2
FAM111B	ENST00000529618.5	c.726dup	p.Ala243SerfsTer9	frameshift_variant	3/3	1		A2
FAM111B	ENST00000411426.1	c.726dup	p.Ala243SerfsTer9	frameshift_variant	2/2	4		A2
FAM111B	ENST00000620384.1	c.816dup	p.Ala273SerfsTer9	frameshift_variant	2/2	2		P2

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 213 AN: 137120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00153

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000619

Gnomad SAS AF: 0.000688

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000827

Gnomad OTH AF: 0.00106

GnomAD4 exome AF: 0.00126 AC: 1618 AN: 1279448 Hom.: 0 Cov.: 33 AF XY: 0.00128 AC XY: 815 AN XY: 636270

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.00254

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.000305

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.000594

Gnomad4 NFE exome AF: 0.000932

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00155 AC: 213 AN: 137194 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 109 AN XY: 66328

Gnomad4 AFR AF: 0.00266

Gnomad4 AMR AF: 0.00153

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000620

Gnomad4 SAS AF: 0.000691

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000827

Gnomad4 OTH AF: 0.00105

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

FAM111B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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: rs761176801; hg19: chr11-58892376;