rs587777236

Variant names:

• chr11-59125958-T-G
• rs587777236
• NM_198947.4:c.1861T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 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. 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
• Publications: 6 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_198947.4
• 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 VariationId is 120217.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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

Dec 05, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

May be associated with less severe extracutaneous phenotype. Further studies are needed. -

not provided Pathogenic:1

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		0.18
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
Mutation Taster		=25/75	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: rs587777236; hg19: chr11-58893431;