rs74658848

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001312909.2(FAM111A):c.310T>A(p.Leu104Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,614,162 control chromosomes in the GnomAD database, including 47 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0094 ( 24 hom., cov: 33)

Exomes 𝑓: 0.00097 ( 23 hom. )

Consequence

FAM111A
NM_001312909.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.130

Publications

3 publications found

Variant links:

Genes affected

FAM111A (HGNC:24725): (FAM111 trypsin like peptidase A) The protein encoded by this gene is cell-cycle regulated, and has nuclear localization. The C-terminal half of the protein shares homology with trypsin-like peptidases and it contains a PCNA-interacting peptide (PIP) box, that is necessary for its co-localization with proliferating cell nuclear antigen (PCNA). Reduced expression of this gene resulted in DNA replication defects, consistent with the demonstrated role for this gene in Simian Virus 40 (SV40) viral replication. Mutations in this gene have been associated with Kenny-Caffey syndrome (KCS) type 2 and the more severe osteocraniostenosis (OCS, also known as Gracile Bone Dysplasia), both characterized by short stature, hypoparathyroidism, bone development abnormalities, and hypocalcemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

FAM111A links:

FAM111A-DT (HGNC:53752): (FAM111A divergent transcript)

FAM111A-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026037097).

BP6

Variant 11-59151978-T-A is Benign according to our data. Variant chr11-59151978-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0094 (1432/152302) while in subpopulation AFR AF = 0.0328 (1363/41558). AF 95% confidence interval is 0.0313. There are 24 homozygotes in GnomAd4. There are 652 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1432 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM111A	NM_001312909.2 link	c.310T>A	p.Leu104Ile	missense_variant	Exon 6 of 6	ENST00000675163.1	NP_001299838.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM111A	ENST00000675163.1 link	c.310T>A	p.Leu104Ile	missense_variant	Exon 6 of 6		NM_001312909.2	ENSP00000501952.1

Frequencies

GnomAD3 genomes

AF:

0.00935

AC:

1423

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00242

AC:

608

AN:

251268

AF XY:

0.00164

show subpopulations

Gnomad AFR exome

AF:

0.0342

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000967

AC:

1413

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000853

AC XY:

620

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0345

AC:

1155

AN:

33470

American (AMR)

AF:

0.00123

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000594

AC:

AN:

1112008

Other (OTH)

AF:

0.00210

AC:

127

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

165

248

330

413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00940

AC:

1432

AN:

152302

Hom.:

Cov.:

AF XY:

0.00876

AC XY:

652

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0328

AC:

1363

AN:

41558

American (AMR)

AF:

0.00327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

142

214

285

356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00145

Hom.:

Bravo

AF:

0.0105

ESP6500AA

AF:

0.0329

AC:

145

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00302

AC:

367

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 02, 2025

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.5

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.010

T;T;.;T;T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.65

.;T;T;.;.;.

MetaRNN

Benign

0.0026

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M;.;M;M;M

PhyloP100

0.13

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.20

N;N;N;N;N;N

REVEL

Benign

0.051

Sift

Benign

0.38

T;T;T;T;T;T

Sift4G

Benign

0.85

T;T;T;T;T;T

Polyphen

0.91

P;P;.;P;P;P

Vest4

0.11

MVP

0.29

MPC

0.094

ClinPred

0.023

GERP RS

3.8

Varity_R

0.041

gMVP

0.14

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over