NM_198947.4:c.280C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_198947.4(FAM111B):c.280C>T(p.Arg94Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000285 in 1,613,588 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R94G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 1 hom. )

Consequence

FAM111B
NM_198947.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.15

Publications

3 publications found

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]

FAM111B Gene-Disease associations (from GenCC):

hereditary sclerosing poikiloderma with tendon and pulmonary involvement
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet

FAM111B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005990982).

BP6

Variant 11-59124377-C-T is Benign according to our data. Variant chr11-59124377-C-T is described in ClinVar as Benign. ClinVar VariationId is 3050428.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 20 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198947.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM111B	NM_198947.4	MANE Select	c.280C>T	p.Arg94Cys	missense	Exon 4 of 4	NP_945185.1	Q6SJ93-1
FAM111B	NM_001142703.2		c.190C>T	p.Arg64Cys	missense	Exon 3 of 3	NP_001136175.1	Q6SJ93-2
FAM111B	NM_001142704.2		c.190C>T	p.Arg64Cys	missense	Exon 2 of 2	NP_001136176.1	Q6SJ93-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM111B	ENST00000343597.4	TSL:1 MANE Select	c.280C>T	p.Arg94Cys	missense	Exon 4 of 4	ENSP00000341565.3	Q6SJ93-1
FAM111B	ENST00000529618.5	TSL:1	c.190C>T	p.Arg64Cys	missense	Exon 3 of 3	ENSP00000432875.1	Q6SJ93-2
FAM111B	ENST00000620384.1	TSL:2	c.280C>T	p.Arg94Cys	missense	Exon 2 of 2	ENSP00000483456.1	Q6SJ93-1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000626

AC:

157

AN:

250842

AF XY:

0.000900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000301

AC:

440

AN:

1461466

Hom.:

Cov.:

AF XY:

0.000435

AC XY:

316

AN XY:

727022

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.000202

AC:

AN:

39686

South Asian (SAS)

AF:

0.00458

AC:

395

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111824

Other (OTH)

AF:

0.000348

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000131

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41502

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00395

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000667

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

FAM111B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

9.0

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.076

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.69

M_CAP

Benign

0.0069

MetaRNN

Benign

0.0060

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.6

PhyloP100

-1.1

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.062

Sift

Benign

0.20

Sift4G

Benign

0.084

Polyphen

0.032

Vest4

0.16

MutPred

0.40

Loss of solvent accessibility (P = 0.002)

MVP

0.31

MPC

0.25

ClinPred

0.049

GERP RS

0.38

Varity_R

0.048

gMVP

0.13

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over