9-14898163-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001379081.2(FREM1):c.-268+11751A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 152,154 control chromosomes in the GnomAD database, including 3,849 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 0.18 (3849 hom., cov: 33)
• Consequence: FREM1 NM_001379081.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.604

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM1	NM_001379081.2	c.-268+11751A>C		intron_variant		ENST00000380880.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM1	ENST00000380880.4	c.-268+11751A>C		intron_variant		5	NM_001379081.2	P1
FREM1	ENST00000380875.7	c.-268+11751A>C		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27553 AN: 152036 Hom.: 3836 Cov.: 33

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0787

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.0765

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0891

Gnomad OTH AF: 0.154

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

GnomAD4 genome AF: 0.181 AC: 27584 AN: 152154 Hom.: 3849 Cov.: 33 AF XY: 0.179 AC XY: 13286 AN XY: 74392

Gnomad4 AFR AF: 0.377

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.0787

Gnomad4 EAS AF: 0.347

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.0765

Gnomad4 NFE AF: 0.0891

Gnomad4 OTH AF: 0.152

Alfa AF: 0.0994 Hom.: 2360

Bravo AF: 0.195

Asia WGS AF: 0.217 AC: 753 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	2.5
Dann	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs10961780; hg19: chr9-14898161;