11-59124768-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198947.4(FAM111B):c.671C>G(p.Ala224Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM111B NM_198947.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM111B	NM_198947.4	c.671C>G	p.Ala224Gly	missense_variant	4/4	ENST00000343597.4
FAM111B	NM_001142703.2	c.581C>G	p.Ala194Gly	missense_variant	3/3
FAM111B	NM_001142704.2	c.581C>G	p.Ala194Gly	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM111B	ENST00000343597.4	c.671C>G	p.Ala224Gly	missense_variant	4/4	1	NM_198947.4	P2
FAM111B	ENST00000529618.5	c.581C>G	p.Ala194Gly	missense_variant	3/3	1		A2
FAM111B	ENST00000620384.1	c.671C>G	p.Ala224Gly	missense_variant	2/2	2		P2
FAM111B	ENST00000411426.1	c.581C>G	p.Ala194Gly	missense_variant	2/2	4		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461648 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727120

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary sclerosing poikiloderma with tendon and pulmonary involvement Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 31, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.043
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.60	T;.;.;T
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.1	D;D;D;.
REVEL	Benign	0.13
Sift	Uncertain	0.013	D;D;D;.
Sift4G	Uncertain	0.023	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.54
MutPred		0.23		.;.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.67
MPC		0.32
ClinPred		0.94	D
GERP RS		3.6
Varity_R		0.17
gMVP		0.29

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: rs1859986458; hg19: chr11-58892241;