chr11-59124815-T-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_198947.4(FAM111B):c.718T>A(p.Trp240Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
FAM111B
NM_198947.4 missense
NM_198947.4 missense
Scores
5
3
9
Clinical Significance
Conservation
PhyloP100: 2.71
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.876
BS2
?
High AC in GnomAdExome at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FAM111B | NM_198947.4 | c.718T>A | p.Trp240Arg | missense_variant | 4/4 | ENST00000343597.4 | |
FAM111B | NM_001142703.2 | c.628T>A | p.Trp210Arg | missense_variant | 3/3 | ||
FAM111B | NM_001142704.2 | c.628T>A | p.Trp210Arg | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FAM111B | ENST00000343597.4 | c.718T>A | p.Trp240Arg | missense_variant | 4/4 | 1 | NM_198947.4 | P2 | |
FAM111B | ENST00000529618.5 | c.628T>A | p.Trp210Arg | missense_variant | 3/3 | 1 | A2 | ||
FAM111B | ENST00000620384.1 | c.718T>A | p.Trp240Arg | missense_variant | 2/2 | 2 | P2 | ||
FAM111B | ENST00000411426.1 | c.628T>A | p.Trp210Arg | missense_variant | 2/2 | 4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000264 AC: 4AN: 151748Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250730Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135548
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461684Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727140
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 151866Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74202
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 23, 2023 | The c.718T>A (p.W240R) alteration is located in exon 4 (coding exon 2) of the FAM111B gene. This alteration results from a T to A substitution at nucleotide position 718, causing the tryptophan (W) at amino acid position 240 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;.;T
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D;.
REVEL
Uncertain
Sift
Pathogenic
D;D;D;.
Sift4G
Pathogenic
D;D;D;D
Polyphen
1.0
.;.;D;D
Vest4
MutPred
0.57
.;.;Gain of disorder (P = 0.0017);Gain of disorder (P = 0.0017);
MVP
MPC
0.44
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at