rs1449044774

Variant names:

• chr11-59124180-A-G
• rs1449044774
• NM_198947.4:c.83A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_198947.4(FAM111B):​c.83A>G​(p.Asp28Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,442,888 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (1 hom.)
• Consequence: FAM111B NM_198947.4 missense, splice_region
• Scores: Splicing: ADA: 0.00008140
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0810
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.059001952).
• BS2: High AC in GnomAdExome4 at 15 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM111B	NM_198947.4	MANE Select	c.83A>G	p.Asp28Gly	missense splice_region	Exon 4 of 4	NP_945185.1	Q6SJ93-1
	FAM111B	NM_001142703.2		c.-8A>G		splice_region	Exon 3 of 3	NP_001136175.1	Q6SJ93-2
	FAM111B	NM_001142704.2		c.-8A>G		splice_region	Exon 2 of 2	NP_001136176.1	Q6SJ93-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM111B	ENST00000343597.4	TSL:1 MANE Select	c.83A>G	p.Asp28Gly	missense splice_region	Exon 4 of 4	ENSP00000341565.3	Q6SJ93-1
	FAM111B	ENST00000529618.5	TSL:1	c.-8A>G		splice_region	Exon 3 of 3	ENSP00000432875.1	Q6SJ93-2
	FAM111B	ENST00000529618.5	TSL:1	c.-8A>G		5_prime_UTR	Exon 3 of 3	ENSP00000432875.1	Q6SJ93-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 238270 AF XY: 0.00000777

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: 0.00

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.0000104 AC: 15 AN: 1442888 Hom.: 1 Cov.: 31 AF XY: 0.0000112 AC XY: 8 AN XY: 715954

African (AFR) AF: 0.00 AC: 0 AN: 32672

American (AMR) AF: 0.00 AC: 0 AN: 41736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25290

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.00 AC: 0 AN: 83024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.0000118 AC: 13 AN: 1102560

Other (OTH) AF: 0.0000336 AC: 2 AN: 59598

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000771 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.77
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0082	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.081
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.031
Sift	Benign	0.30	T
Sift4G	Benign	0.30	T
Polyphen		0.14	B
Vest4		0.12
MVP		0.23
MPC		0.069
ClinPred		0.031	T
GERP RS		2.2
Varity_R		0.035
gMVP		0.17
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000081
dbscSNV1_RF	Benign	0.024
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

Other links and lift over

dbSNP: rs1449044774; hg19: chr11-58891653;