chr13-38692347-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_207361.6(FREM2):​c.5003G>C​(p.Arg1668Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1668H) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FREM2
NM_207361.6 missense

Scores

3
9
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.93

Publications

0 publications found
Variant links:
Genes affected
FREM2 (HGNC:25396): (FRAS1 related extracellular matrix 2) This gene encodes an integral membrane protein containing numerous CSPG (chondroitin sulfate proteoglycan element) repeats and Calx-beta domains. The encoded protein localizes to the basement membrane, forming a ternary complex that plays a role in epidermal-dermal interactions. This protein is important for the integrity of skin and renal epithelia. Mutations in this gene are associated with Fraser syndrome. [provided by RefSeq, Apr 2014]
FREM2 Gene-Disease associations (from GenCC):
  • Fraser syndrome 2
    Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
  • Fraser syndrome 1
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • renal agenesis, unilateral
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Fraser syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FREM2NM_207361.6 linkc.5003G>C p.Arg1668Pro missense_variant Exon 1 of 24 ENST00000280481.9 NP_997244.4 Q5SZK8-1
FREM2XM_017020554.2 linkc.5003G>C p.Arg1668Pro missense_variant Exon 1 of 3 XP_016876043.1
FREM2XR_941571.3 linkn.5271G>C non_coding_transcript_exon_variant Exon 1 of 8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FREM2ENST00000280481.9 linkc.5003G>C p.Arg1668Pro missense_variant Exon 1 of 24 1 NM_207361.6 ENSP00000280481.7 Q5SZK8-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.89e-7
AC:
1
AN:
1451690
Hom.:
0
Cov.:
34
AF XY:
0.00000139
AC XY:
1
AN XY:
721048
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33054
American (AMR)
AF:
0.00
AC:
0
AN:
43770
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25368
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39582
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84886
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53066
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5696
European-Non Finnish (NFE)
AF:
9.04e-7
AC:
1
AN:
1106456
Other (OTH)
AF:
0.00
AC:
0
AN:
59812
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.62
BayesDel_addAF
Uncertain
0.084
D
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
25
DANN
Uncertain
1.0
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.97
D
M_CAP
Benign
0.029
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Benign
-0.30
T
PhyloP100
4.9
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-3.9
D
REVEL
Uncertain
0.33
Sift
Uncertain
0.016
D
Sift4G
Uncertain
0.022
D
Vest4
0.86
MutPred
0.50
Gain of glycosylation at R1668 (P = 0.0646);
MVP
0.64
MPC
0.25
ClinPred
0.99
D
GERP RS
4.5
gMVP
0.89
Mutation Taster
=49/51
disease causing

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

Other links and lift over

dbSNP: rs1868463; hg19: chr13-39266484; API