9-14841389-C-T

Variant names:

• chr9-14841389-C-T
• rs1552896
• NM_001379081.2:c.1881+58G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001379081.2(FREM1):​c.1881+58G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000812 in 1,231,644 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: FREM1 NM_001379081.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.370
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• BNAR syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379081.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	NM_001379081.2	MANE Select	c.1881+58G>A		intron	N/A	NP_001366010.1	Q5H8C1-1
	FREM1	NM_144966.7		c.1881+58G>A		intron	N/A	NP_659403.4
	FREM1	NR_163238.2		n.2697+58G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	ENST00000380880.4	TSL:5 MANE Select	c.1881+58G>A		intron	N/A	ENSP00000370262.3	Q5H8C1-1
	FREM1	ENST00000380875.7	TSL:1	n.1881+58G>A		intron	N/A	ENSP00000370257.3	F8WE85
	FREM1	ENST00000895028.1		c.1881+58G>A		intron	N/A	ENSP00000565087.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.12e-7 AC: 1 AN: 1231644 Hom.: 0 AF XY: 0.00000165 AC XY: 1 AN XY: 604990

African (AFR) AF: 0.00 AC: 0 AN: 28030

American (AMR) AF: 0.00 AC: 0 AN: 29648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21098

East Asian (EAS) AF: 0.00 AC: 0 AN: 36306

South Asian (SAS) AF: 0.00 AC: 0 AN: 54744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5044

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 957996

Other (OTH) AF: 0.00 AC: 0 AN: 50598

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.1
DANN	Benign	0.70
PhyloP100		-0.37

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: rs1552896; hg19: chr9-14841387;