rs886039851

Variant names:

• chr11-59125357-AAAG-A
• rs886039851
• NM_198947.4:c.1262_1264delAGA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_198947.4(FAM111B):​c.1262_1264delAGA​(p.Lys421del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAM111B NM_198947.4 disruptive_inframe_deletion
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.458
• Publications: 4 publications found

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]

FAM111B Gene-Disease associations (from GenCC):

• hereditary sclerosing poikiloderma with tendon and pulmonary involvement

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_198947.4. Strenght limited to Supporting due to length of the change: 1aa.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198947.4. 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
	FAM111B	NM_198947.4	MANE Select	c.1262_1264delAGA	p.Lys421del	disruptive_inframe_deletion	Exon 4 of 4	NP_945185.1	Q6SJ93-1
	FAM111B	NM_001142703.2		c.1172_1174delAGA	p.Lys391del	disruptive_inframe_deletion	Exon 3 of 3	NP_001136175.1	Q6SJ93-2
	FAM111B	NM_001142704.2		c.1172_1174delAGA	p.Lys391del	disruptive_inframe_deletion	Exon 2 of 2	NP_001136176.1	Q6SJ93-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM111B	ENST00000343597.4	TSL:1 MANE Select	c.1262_1264delAGA	p.Lys421del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000341565.3	Q6SJ93-1
	FAM111B	ENST00000529618.5	TSL:1	c.1172_1174delAGA	p.Lys391del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000432875.1	Q6SJ93-2
	FAM111B	ENST00000620384.1	TSL:2	c.1262_1264delAGA	p.Lys421del	disruptive_inframe_deletion	Exon 2 of 2	ENSP00000483456.1	Q6SJ93-1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Hereditary sclerosing poikiloderma with tendon and pulmonary involvement (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.46
Mutation Taster		=82/18	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886039851; hg19: chr11-58892830;