NM_198947.4:c.1861T>G

Variant names:

• chr11-59125958-T-G
• rs587777236
• NM_198947.4:c.1861T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_198947.4(FAM111B):​c.1861T>G​(p.Tyr621Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAM111B NM_198947.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 0.178
• Publications: 6 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_198947.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-59125958-T-G is Pathogenic according to our data. Variant chr11-59125958-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 120217.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1861T>G	p.Tyr621Asp	missense	Exon 4 of 4	NP_945185.1	Q6SJ93-1
	FAM111B	NM_001142703.2		c.1771T>G	p.Tyr591Asp	missense	Exon 3 of 3	NP_001136175.1	Q6SJ93-2
	FAM111B	NM_001142704.2		c.1771T>G	p.Tyr591Asp	missense	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.1861T>G	p.Tyr621Asp	missense	Exon 4 of 4	ENSP00000341565.3	Q6SJ93-1
	FAM111B	ENST00000529618.5	TSL:1	c.1771T>G	p.Tyr591Asp	missense	Exon 3 of 3	ENSP00000432875.1	Q6SJ93-2
	FAM111B	ENST00000620384.1	TSL:2	c.1861T>G	p.Tyr621Asp	missense	Exon 2 of 2	ENSP00000483456.1	Q6SJ93-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary sclerosing poikiloderma with tendon and pulmonary involvement (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	10
DANN	Benign	0.80
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.33	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.18
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.69
Sift	Benign	0.14	T
Sift4G	Benign	0.17	T
Polyphen		0.17	B
Vest4		0.68
MutPred		0.54		Loss of sheet (P = 0.0357)
MVP		0.55
MPC		0.11
ClinPred		0.15	T
GERP RS		-0.42
Varity_R		0.27
gMVP		0.86
Mutation Taster		=25/75	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777236; hg19: chr11-58893431;