9-14737256-AT-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001379081.2(FREM1):​c.*139delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 572,062 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0026 ( 2 hom. )

Consequence

FREM1
NM_001379081.2 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.125
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_benign. Variant got -5 ACMG points.

BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00204 (310/152314) while in subpopulation SAS AF= 0.00435 (21/4828). AF 95% confidence interval is 0.00291. There are 1 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FREM1NM_001379081.2 linkc.*139delA 3_prime_UTR_variant Exon 37 of 37 ENST00000380880.4 NP_001366010.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FREM1ENST00000380880 linkc.*139delA 3_prime_UTR_variant Exon 37 of 37 5 NM_001379081.2 ENSP00000370262.3 Q5H8C1-1
FREM1ENST00000380894 linkc.*139delA 3_prime_UTR_variant Exon 14 of 14 1 ENSP00000370278.1 Q5H8C1-2
FREM1ENST00000380875.7 linkn.*1245delA non_coding_transcript_exon_variant Exon 31 of 31 1 ENSP00000370257.3 F8WE85
FREM1ENST00000380875.7 linkn.*1245delA 3_prime_UTR_variant Exon 31 of 31 1 ENSP00000370257.3 F8WE85

Frequencies

GnomAD3 genomes
AF:
0.00204
AC:
310
AN:
152196
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000627
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000981
Gnomad ASJ
AF:
0.00606
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00435
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00322
Gnomad OTH
AF:
0.00143
GnomAD4 exome
AF:
0.00262
AC:
1098
AN:
419748
Hom.:
2
Cov.:
5
AF XY:
0.00277
AC XY:
599
AN XY:
216588
show subpopulations
Gnomad4 AFR exome
AF:
0.000436
Gnomad4 AMR exome
AF:
0.00100
Gnomad4 ASJ exome
AF:
0.00716
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00370
Gnomad4 FIN exome
AF:
0.000485
Gnomad4 NFE exome
AF:
0.00302
Gnomad4 OTH exome
AF:
0.00273
GnomAD4 genome
AF:
0.00204
AC:
310
AN:
152314
Hom.:
1
Cov.:
32
AF XY:
0.00204
AC XY:
152
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.000625
Gnomad4 AMR
AF:
0.000980
Gnomad4 ASJ
AF:
0.00606
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00435
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.00322
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000163
Hom.:
0
Bravo
AF:
0.00203
Asia WGS
AF:
0.00260
AC:
9
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Oculotrichoanal syndrome Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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: rs558465754; hg19: chr9-14737254; API