rs9298708

Variant names:

• chr9-14868314-A-G
• rs9298708
• NM_001379081.2:c.234+430T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001379081.2(FREM1):​c.234+430T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0884 in 152,200 control chromosomes in the GnomAD database, including 1,806 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.088 (1806 hom., cov: 32)
• Consequence: FREM1 NM_001379081.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0130
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2	c.234+430T>C		intron_variant	Intron 2 of 36	ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4	c.234+430T>C		intron_variant	Intron 2 of 36	5	NM_001379081.2	ENSP00000370262.3
FREM1	ENST00000380875.7	n.234+430T>C		intron_variant	Intron 3 of 30	1		ENSP00000370257.3

Frequencies

GnomAD3 genomes AF: 0.0883 AC: 13423 AN: 152082 Hom.: 1801 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0483

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00376

Gnomad OTH AF: 0.0651

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0884 AC: 13453 AN: 152200 Hom.: 1806 Cov.: 32 AF XY: 0.0856 AC XY: 6371 AN XY: 74426

African (AFR) AF: 0.293 AC: 12145 AN: 41482

American (AMR) AF: 0.0485 AC: 742 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5172

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4824

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00376 AC: 256 AN: 68030

Other (OTH) AF: 0.0644 AC: 136 AN: 2112

Alfa AF: 0.0696 Hom.: 211

Bravo AF: 0.102

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.0
DANN	Benign	0.61
PhyloP100		-0.013
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: rs9298708; hg19: chr9-14868312;