9-14737248-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001379081.2(FREM1):​c.*148A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 567,020 control chromosomes in the GnomAD database, including 351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 277 hom., cov: 32)
Exomes 𝑓: 0.0041 ( 74 hom. )

Consequence

FREM1
NM_001379081.2 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.789
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 9-14737248-T-C is Benign according to our data. Variant chr9-14737248-T-C is described in ClinVar as [Benign]. Clinvar id is 366095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FREM1NM_001379081.2 linkc.*148A>G 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.*148A>G 3_prime_UTR_variant Exon 37 of 37 5 NM_001379081.2 ENSP00000370262.3 Q5H8C1-1
FREM1ENST00000380894 linkc.*148A>G 3_prime_UTR_variant Exon 14 of 14 1 ENSP00000370278.1 Q5H8C1-2
FREM1ENST00000380875.7 linkn.*1254A>G non_coding_transcript_exon_variant Exon 31 of 31 1 ENSP00000370257.3 F8WE85
FREM1ENST00000380875.7 linkn.*1254A>G 3_prime_UTR_variant Exon 31 of 31 1 ENSP00000370257.3 F8WE85

Frequencies

GnomAD3 genomes
AF:
0.0340
AC:
5175
AN:
152154
Hom.:
277
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.119
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0113
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.000382
Gnomad OTH
AF:
0.0215
GnomAD4 exome
AF:
0.00409
AC:
1698
AN:
414748
Hom.:
74
Cov.:
5
AF XY:
0.00341
AC XY:
731
AN XY:
214528
show subpopulations
Gnomad4 AFR exome
AF:
0.113
Gnomad4 AMR exome
AF:
0.00759
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000670
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000327
Gnomad4 OTH exome
AF:
0.00812
GnomAD4 genome
AF:
0.0340
AC:
5170
AN:
152272
Hom.:
277
Cov.:
32
AF XY:
0.0326
AC XY:
2429
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.119
Gnomad4 AMR
AF:
0.0112
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000382
Gnomad4 OTH
AF:
0.0208
Alfa
AF:
0.0132
Hom.:
35
Bravo
AF:
0.0388
Asia WGS
AF:
0.00433
AC:
15
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
May 12, 2021
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Oculotrichoanal syndrome Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
5.2
DANN
Benign
0.84

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: rs11999446; hg19: chr9-14737246; API