9-14890270-T-C

Variant names:

• chr9-14890270-T-C
• rs1996893
• NM_001379081.2:c.-268+19644A>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.-268+19644A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 152,178 control chromosomes in the GnomAD database, including 32,589 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 0.63 (32589 hom., cov: 33)
• Consequence: FREM1 NM_001379081.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0360
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2	c.-268+19644A>G		intron_variant	Intron 1 of 36	ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4	c.-268+19644A>G		intron_variant	Intron 1 of 36	5	NM_001379081.2	ENSP00000370262.3
FREM1	ENST00000380875.7	n.-268+19644A>G		intron_variant	Intron 2 of 30	1		ENSP00000370257.3

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95861 AN: 152060 Hom.: 32536 Cov.: 33

Gnomad AFR AF: 0.879

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.498

Gnomad EAS AF: 0.893

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.602

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

GnomAD4 genome AF: 0.631 AC: 95973 AN: 152178 Hom.: 32589 Cov.: 33 AF XY: 0.633 AC XY: 47085 AN XY: 74410

African (AFR) AF: 0.879 AC: 36513 AN: 41554

American (AMR) AF: 0.650 AC: 9940 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 1728 AN: 3470

East Asian (EAS) AF: 0.893 AC: 4625 AN: 5178

South Asian (SAS) AF: 0.574 AC: 2776 AN: 4834

European-Finnish (FIN) AF: 0.524 AC: 5543 AN: 10576

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.484 AC: 32900 AN: 67950

Other (OTH) AF: 0.607 AC: 1284 AN: 2116

Alfa AF: 0.534 Hom.: 38896

Bravo AF: 0.654

Asia WGS AF: 0.743 AC: 2581 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.8
DANN	Benign	0.85
PhyloP100		-0.036
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: rs1996893; hg19: chr9-14890268;