11-59124317-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198947.4(FAM111B):​c.220T>A​(p.Leu74Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FAM111B
NM_198947.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.30
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09297931).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FAM111BNM_198947.4 linkc.220T>A p.Leu74Met missense_variant Exon 4 of 4 ENST00000343597.4 NP_945185.1 Q6SJ93-1
FAM111BNM_001142703.2 linkc.130T>A p.Leu44Met missense_variant Exon 3 of 3 NP_001136175.1 Q6SJ93-2
FAM111BNM_001142704.2 linkc.130T>A p.Leu44Met missense_variant Exon 2 of 2 NP_001136176.1 Q6SJ93-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FAM111BENST00000343597.4 linkc.220T>A p.Leu74Met missense_variant Exon 4 of 4 1 NM_198947.4 ENSP00000341565.3 Q6SJ93-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461614
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727110
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
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

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
May 28, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.220T>A (p.L74M) 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 220, causing the leucine (L) at amino acid position 74 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
0.014
DANN
Benign
0.94
DEOGEN2
Benign
0.019
.;.;.;T;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.0061
N
LIST_S2
Benign
0.33
T;.;T;.;T
M_CAP
Benign
0.0053
T
MetaRNN
Benign
0.093
T;T;T;T;T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
1.6
.;.;.;L;L
PrimateAI
Benign
0.27
T
PROVEAN
Benign
0.18
N;N;N;N;.
REVEL
Benign
0.090
Sift
Benign
0.060
T;T;D;T;.
Sift4G
Benign
0.13
T;T;T;T;T
Polyphen
0.87
.;.;.;P;P
Vest4
0.10
MutPred
0.14
.;.;.;Gain of disorder (P = 0.0732);Gain of disorder (P = 0.0732);
MVP
0.20
MPC
0.12
ClinPred
0.35
T
GERP RS
-5.5
Varity_R
0.039
gMVP
0.046

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-58891790; API