rs587777236

Positions:

• chr11-59125958-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_198947.4(FAM111B):​c.1861T>G​(p.Tyr621Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAM111B NM_198947.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 0.178

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-59125958-T-G is Pathogenic according to our data. Variant chr11-59125958-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 120217.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM111B	NM_198947.4	c.1861T>G	p.Tyr621Asp	missense_variant	4/4	ENST00000343597.4	NP_945185.1
FAM111B	NM_001142703.2	c.1771T>G	p.Tyr591Asp	missense_variant	3/3		NP_001136175.1
FAM111B	NM_001142704.2	c.1771T>G	p.Tyr591Asp	missense_variant	2/2		NP_001136176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM111B	ENST00000343597.4	c.1861T>G	p.Tyr621Asp	missense_variant	4/4	1	NM_198947.4	ENSP00000341565.3
FAM111B	ENST00000529618.5	c.1771T>G	p.Tyr591Asp	missense_variant	3/3	1		ENSP00000432875.1
FAM111B	ENST00000620384.1	c.1861T>G	p.Tyr621Asp	missense_variant	2/2	2		ENSP00000483456.1
FAM111B	ENST00000411426.1	c.1771T>G	p.Tyr591Asp	missense_variant	2/2	4		ENSP00000393855.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary sclerosing poikiloderma with tendon and pulmonary involvement Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 05, 2013	- -
not provided, no classification provided	literature only	GeneReviews	-	May be associated with less severe extracutaneous phenotype. Further studies are needed. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	10
DANN	Benign	0.80
DEOGEN2	Uncertain	0.67	.;.;D;D
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.33	T;.;.;T
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.0	.;.;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.6	D;D;D;.
REVEL	Pathogenic	0.69
Sift	Benign	0.14	T;T;T;.
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.17	.;.;B;B
Vest4		0.68
MutPred		0.54		.;.;Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		0.55
MPC		0.11
ClinPred		0.15	T
GERP RS		-0.42
Varity_R		0.27
gMVP		0.86

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: rs587777236; hg19: chr11-58893431;