9-14854074-C-T

Variant names:

• chr9-14854074-C-T
• rs2151206
• NM_001379081.2:c.829-2467G>A

Variant summary

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

The NM_001379081.2(FREM1):​c.829-2467G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 151,992 control chromosomes in the GnomAD database, including 20,929 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 0.50 (20929 hom., cov: 32)
• Consequence: FREM1 NM_001379081.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.131
• Publications: 5 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 (SAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2	c.829-2467G>A		intron_variant	Intron 5 of 36	ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4	c.829-2467G>A		intron_variant	Intron 5 of 36	5	NM_001379081.2	ENSP00000370262.3
FREM1	ENST00000380875.7	n.829-2467G>A		intron_variant	Intron 6 of 30	1		ENSP00000370257.3

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75628 AN: 151874 Hom.: 20930 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.514

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

GnomAD4 genome AF: 0.498 AC: 75623 AN: 151992 Hom.: 20929 Cov.: 32 AF XY: 0.499 AC XY: 37074 AN XY: 74302

African (AFR) AF: 0.261 AC: 10838 AN: 41476

American (AMR) AF: 0.473 AC: 7224 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2177 AN: 3470

East Asian (EAS) AF: 0.280 AC: 1449 AN: 5170

South Asian (SAS) AF: 0.665 AC: 3199 AN: 4814

European-Finnish (FIN) AF: 0.612 AC: 6451 AN: 10544

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.627 AC: 42571 AN: 67936

Other (OTH) AF: 0.509 AC: 1072 AN: 2108

Alfa AF: 0.592 Hom.: 10650

Bravo AF: 0.471

Asia WGS AF: 0.442 AC: 1542 AN: 3476

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	0.68
PhyloP100		-0.13
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: rs2151206; hg19: chr9-14854072;