rs2131880

Variant names:

• chr9-14776029-C-T
• rs2131880
• NM_001379081.2:c.4617G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001379081.2(FREM1):​c.4617G>A​(p.Ala1539Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,790 control chromosomes in the GnomAD database, including 21,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1766 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19717 hom.)
• Consequence: FREM1 NM_001379081.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.39
• Publications: 14 publications found

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]

FREM1 Gene-Disease associations (from GenCC):

• oculotrichoanal syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• BNAR syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• isolated trigonocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• trigonocephaly 2

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 9-14776029-C-T is Benign according to our data. Variant chr9-14776029-C-T is described in ClinVar as Benign. ClinVar VariationId is 262539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2	c.4617G>A	p.Ala1539Ala	synonymous_variant	Exon 25 of 37	ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4	c.4617G>A	p.Ala1539Ala	synonymous_variant	Exon 25 of 37	5	NM_001379081.2	ENSP00000370262.3

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21694 AN: 152054 Hom.: 1762 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.0852

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.150

GnomAD2 exomes AF: 0.131 AC: 32500 AN: 248776 AF XY: 0.131

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.0787

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.0261

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.159 AC: 232908 AN: 1461618 Hom.: 19717 Cov.: 39 AF XY: 0.157 AC XY: 114494 AN XY: 727090

African (AFR) AF: 0.136 AC: 4551 AN: 33478

American (AMR) AF: 0.0842 AC: 3764 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3577 AN: 26136

East Asian (EAS) AF: 0.0240 AC: 954 AN: 39696

South Asian (SAS) AF: 0.0882 AC: 7606 AN: 86258

European-Finnish (FIN) AF: 0.131 AC: 6978 AN: 53400

Middle Eastern (MID) AF: 0.130 AC: 751 AN: 5768

European-Non Finnish (NFE) AF: 0.176 AC: 195698 AN: 1111784

Other (OTH) AF: 0.150 AC: 9029 AN: 60374

GnomAD4 genome AF: 0.143 AC: 21704 AN: 152172 Hom.: 1766 Cov.: 33 AF XY: 0.138 AC XY: 10283 AN XY: 74392

African (AFR) AF: 0.134 AC: 5572 AN: 41520

American (AMR) AF: 0.120 AC: 1839 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 452 AN: 3470

East Asian (EAS) AF: 0.0281 AC: 145 AN: 5168

South Asian (SAS) AF: 0.0852 AC: 411 AN: 4822

European-Finnish (FIN) AF: 0.124 AC: 1318 AN: 10606

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11538 AN: 67984

Other (OTH) AF: 0.147 AC: 310 AN: 2110

Alfa AF: 0.156 Hom.: 959

Bravo AF: 0.142

Asia WGS AF: 0.0550 AC: 194 AN: 3478

EpiCase AF: 0.177

EpiControl AF: 0.172

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 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:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.70
DANN	Benign	0.34
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2131880; hg19: chr9-14776027; COSMIC: COSV66521098; COSMIC: COSV66521098;