rs587777238

Variant names:

• chr11-59125980-G-A
• rs587777238
• NM_198947.4:c.1883G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_198947.4(FAM111B):​c.1883G>A​(p.Ser628Asn) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S628R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAM111B NM_198947.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.50
• Publications: 9 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: Uncertain_significance. The variant received 5 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, 4 uncertain in NM_198947.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-59125980-G-A is Pathogenic according to our data. Variant chr11-59125980-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 120219.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM111B	NM_198947.4	c.1883G>A	p.Ser628Asn	missense_variant	Exon 4 of 4	ENST00000343597.4	NP_945185.1
FAM111B	NM_001142703.2	c.1793G>A	p.Ser598Asn	missense_variant	Exon 3 of 3		NP_001136175.1
FAM111B	NM_001142704.2	c.1793G>A	p.Ser598Asn	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.1883G>A	p.Ser628Asn	missense_variant	Exon 4 of 4	1	NM_198947.4	ENSP00000341565.3
FAM111B	ENST00000529618.5	c.1793G>A	p.Ser598Asn	missense_variant	Exon 3 of 3	1		ENSP00000432875.1
FAM111B	ENST00000620384.1	c.1883G>A	p.Ser628Asn	missense_variant	Exon 2 of 2	2		ENSP00000483456.1
FAM111B	ENST00000411426.1	c.1793G>A	p.Ser598Asn	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: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

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

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;.;T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.53	T;.;.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Uncertain	0.045	D
MutationAssessor	Uncertain	2.7	.;.;M;M
PhyloP100		1.5
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.5	D;D;D;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0030	D;D;D;.
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.26
MutPred		0.67		.;.;Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);
MVP		0.92
MPC		0.28
ClinPred		0.95	D
GERP RS		3.8
Varity_R		0.22
gMVP		0.64
Mutation Taster		=3/97	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: rs587777238; hg19: chr11-58893453;