NM_001379081.2:c.3981+1297A>G

Variant names:

• chr9-14791446-T-C
• rs16932288
• NM_001379081.2:c.3981+1297A>G

Variant summary

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

The NM_001379081.2(FREM1):​c.3981+1297A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 152,284 control chromosomes in the GnomAD database, including 490 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 0.050 (490 hom., cov: 33)
• Consequence: FREM1 NM_001379081.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.413
• Publications: 1 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2	c.3981+1297A>G		intron_variant	Intron 22 of 36	ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4	c.3981+1297A>G		intron_variant	Intron 22 of 36	5	NM_001379081.2	ENSP00000370262.3
FREM1	ENST00000380875.7	n.3981+1297A>G		intron_variant	Intron 23 of 30	1		ENSP00000370257.3
FREM1	ENST00000466679.1	n.59+1297A>G		intron_variant	Intron 1 of 3	3
FREM1	ENST00000497634.2	n.142+1297A>G		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7574 AN: 152166 Hom.: 490 Cov.: 33

Gnomad AFR AF: 0.0613

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.0401

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0679

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

GnomAD4 genome AF: 0.0498 AC: 7587 AN: 152284 Hom.: 490 Cov.: 33 AF XY: 0.0532 AC XY: 3964 AN XY: 74458

African (AFR) AF: 0.0615 AC: 2554 AN: 41546

American (AMR) AF: 0.136 AC: 2079 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 239 AN: 3470

East Asian (EAS) AF: 0.290 AC: 1497 AN: 5162

South Asian (SAS) AF: 0.0400 AC: 193 AN: 4828

European-Finnish (FIN) AF: 0.0126 AC: 134 AN: 10626

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0106 AC: 719 AN: 68030

Other (OTH) AF: 0.0662 AC: 140 AN: 2114

Alfa AF: 0.0362 Hom.: 99

Bravo AF: 0.0619

Asia WGS AF: 0.123 AC: 425 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	9.2
DANN	Benign	0.59
PhyloP100		0.41
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: rs16932288; hg19: chr9-14791444;