9-14792753-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_001379081.2(FREM1):​c.3971T>C​(p.Leu1324Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,596,348 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. L1324R) has been classified as Pathogenic.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

FREM1
NM_001379081.2 missense

Scores

12
5
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.50
Variant links:
Genes affected
FREM1 (HGNC:23399): (FRAS1 related extracellular matrix 1) This gene encodes a basement membrane protein that may play a role in craniofacial and renal development. Mutations in this gene have been associated with bifid nose with or without anorectal and renal anomalies. Alternatively spliced transcript variants encoding different isoforms have been described. PubMed ID 19940113 describes one such variant that initiates transcription within a distinct, internal exon; the resulting shorter isoform (named Toll-like/interleukin-1 receptor regulator, TILRR) is suggested to be a co-receptor of the interleukin 1 receptor family and may regulate receptor function and Toll-like receptor/interleukin 1 receptor signal transduction, contributing to the control of inflammatory response activation. [provided by RefSeq, Apr 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-14792753-A-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FREM1NM_001379081.2 linkc.3971T>C p.Leu1324Pro missense_variant Exon 22 of 37 ENST00000380880.4 NP_001366010.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FREM1ENST00000380880.4 linkc.3971T>C p.Leu1324Pro missense_variant Exon 22 of 37 5 NM_001379081.2 ENSP00000370262.3 Q5H8C1-1
FREM1ENST00000380875.7 linkn.3971T>C non_coding_transcript_exon_variant Exon 23 of 31 1 ENSP00000370257.3 F8WE85
FREM1ENST00000466679.1 linkn.49T>C non_coding_transcript_exon_variant Exon 1 of 4 3
FREM1ENST00000497634.2 linkn.132T>C non_coding_transcript_exon_variant Exon 1 of 3 3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.92e-7
AC:
1
AN:
1444142
Hom.:
0
Cov.:
29
AF XY:
0.00000139
AC XY:
1
AN XY:
716880
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.04e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.50
T;T
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.82
T;.
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Uncertain
0.29
D
MutationAssessor
Pathogenic
3.9
H;H
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-6.2
D;D
REVEL
Pathogenic
0.75
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.97
MutPred
0.74
Gain of disorder (P = 0.0133);Gain of disorder (P = 0.0133);
MVP
0.87
ClinPred
1.0
D
GERP RS
6.1
Varity_R
0.99
gMVP
0.95

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs281875281; hg19: chr9-14792751; API