rs587777237

chr11-59125976-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_198947.4(FAM111B):c.1879A>G(p.Arg627Gly) 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. R627S) 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: 1.01

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 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_198947.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-59125976-A-G is Pathogenic according to our data. Variant chr11-59125976-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 120218.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-59125976-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM111B	NM_198947.4	c.1879A>G	p.Arg627Gly	missense_variant	4/4	ENST00000343597.4
FAM111B	NM_001142703.2	c.1789A>G	p.Arg597Gly	missense_variant	3/3
FAM111B	NM_001142704.2	c.1789A>G	p.Arg597Gly	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM111B	ENST00000343597.4	c.1879A>G	p.Arg627Gly	missense_variant	4/4	1	NM_198947.4	P2
FAM111B	ENST00000529618.5	c.1789A>G	p.Arg597Gly	missense_variant	3/3	1		A2
FAM111B	ENST00000620384.1	c.1879A>G	p.Arg627Gly	missense_variant	2/2	2		P2
FAM111B	ENST00000411426.1	c.1789A>G	p.Arg597Gly	missense_variant	2/2	4		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 05, 2013	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.0052
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.61	T;.;.;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	0.059	D
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.2	D;D;D;.
REVEL	Pathogenic	0.78
Sift	Benign	0.032	D;D;D;.
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.41
MutPred		0.69		.;.;Loss of catalytic residue at R627 (P = 0.1183);Loss of catalytic residue at R627 (P = 0.1183);
MVP		0.87
MPC		0.37
ClinPred		0.97	D
GERP RS		0.70
Varity_R		0.32
gMVP		0.79

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: rs587777237; hg19: chr11-58893449;