11-59109679-C-A

Variant names:

• chr11-59109679-C-A
• rs200783344
• NM_198947.4:c.54C>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_198947.4(FAM111B):​c.54C>A​(p.Asp18Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,611,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: FAM111B NM_198947.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0760

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10538745).
• BS2: High AC in GnomAdExome4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM111B	NM_198947.4	c.54C>A	p.Asp18Glu	missense_variant	Exon 3 of 4	ENST00000343597.4	NP_945185.1
FAM111B	NM_001142703.2	c.-10+967C>A		intron_variant	Intron 2 of 2		NP_001136175.1
FAM111B	NM_001142704.2	c.-10+2383C>A		intron_variant	Intron 1 of 1		NP_001136176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM111B	ENST00000343597.4	c.54C>A	p.Asp18Glu	missense_variant	Exon 3 of 4	1	NM_198947.4	ENSP00000341565.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152134 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000519 AC: 13 AN: 250530 Hom.: 0 AF XY: 0.0000886 AC XY: 12 AN XY: 135438

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000384 AC: 56 AN: 1459806 Hom.: 0 Cov.: 29 AF XY: 0.0000413 AC XY: 30 AN XY: 726260

Gnomad4 AFR exome AF: 0.00

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: 0.0000752

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000216 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.54C>A (p.D18E) alteration is located in exon 3 (coding exon 1) of the FAM111B gene. This alteration results from a C to A substitution at nucleotide position 54, causing the aspartic acid (D) at amino acid position 18 to be replaced by a glutamic acid (E). 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	0.19
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.022	T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.28	.;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.47	N;.
REVEL	Benign	0.078
Sift	Benign	0.12	T;.
Sift4G	Benign	0.53	T;T
Polyphen		0.94	P;P
Vest4		0.088
MutPred		0.084		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.60
MPC		0.10
ClinPred		0.050	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.024

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: rs200783344; hg19: chr11-58877152;