11-59124717-A-C

Variant names:

• chr11-59124717-A-C
• rs1390454543
• NM_198947.4:c.620A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198947.4(FAM111B):​c.620A>C​(p.Lys207Thr) 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 1,461,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FAM111B NM_198947.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.729

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 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=0.10552931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM111B	NM_198947.4	c.620A>C	p.Lys207Thr	missense_variant	Exon 4 of 4	ENST00000343597.4	NP_945185.1
FAM111B	NM_001142703.2	c.530A>C	p.Lys177Thr	missense_variant	Exon 3 of 3		NP_001136175.1
FAM111B	NM_001142704.2	c.530A>C	p.Lys177Thr	missense_variant	Exon 2 of 2		NP_001136176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM111B	ENST00000343597.4	c.620A>C	p.Lys207Thr	missense_variant	Exon 4 of 4	1	NM_198947.4	ENSP00000341565.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250348 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135272

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461410 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726942

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 15, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.620A>C (p.K207T) alteration is located in exon 4 (coding exon 2) of the FAM111B gene. This alteration results from a A to C substitution at nucleotide position 620, causing the lysine (K) at amino acid position 207 to be replaced by a threonine (T). 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	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.69
DANN	Uncertain	0.99
DEOGEN2	Benign	0.082	.;.;T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.52	T;.;.;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;.;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.3	D;D;D;.
REVEL	Benign	0.023
Sift	Uncertain	0.020	D;D;D;.
Sift4G	Benign	0.085	T;T;T;T
Polyphen		0.40	.;.;B;B
Vest4		0.14
MutPred		0.21		.;.;Gain of catalytic residue at K207 (P = 0.0222);Gain of catalytic residue at K207 (P = 0.0222);
MVP		0.44
MPC		0.095
ClinPred		0.093	T
GERP RS		-1.7
Varity_R		0.072
gMVP		0.16

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: rs1390454543; hg19: chr11-58892190;