rs17219005

Positions:

• chr9-14770660-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001379081.2(FREM1):​c.5004C>A​(p.Ile1668=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,611,316 control chromosomes in the GnomAD database, including 115,271 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9425 hom., cov: 32)
  • Exomes 𝑓: 0.37 (105846 hom.)
• Consequence: FREM1 NM_001379081.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0310

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 9-14770660-G-T is Benign according to our data. Variant chr9-14770660-G-T is described in ClinVar as [Benign]. Clinvar id is 262543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14770660-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.031 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM1	NM_001379081.2	c.5004C>A	p.Ile1668=	synonymous_variant	26/37	ENST00000380880.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM1	ENST00000380880.4	c.5004C>A	p.Ile1668=	synonymous_variant	26/37	5	NM_001379081.2	P1

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51703 AN: 151876 Hom.: 9413 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.0745

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.321

GnomAD3 exomes AF: 0.322 AC: 80103 AN: 248932 Hom.: 14495 AF XY: 0.324 AC XY: 43699 AN XY: 135034

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.204

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.0664

Gnomad SAS exome AF: 0.251

Gnomad FIN exome AF: 0.449

Gnomad NFE exome AF: 0.398

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.373 AC: 543891 AN: 1459322 Hom.: 105846 Cov.: 35 AF XY: 0.369 AC XY: 267949 AN XY: 726054

Gnomad4 AFR exome AF: 0.290

Gnomad4 AMR exome AF: 0.215

Gnomad4 ASJ exome AF: 0.303

Gnomad4 EAS exome AF: 0.0805

Gnomad4 SAS exome AF: 0.250

Gnomad4 FIN exome AF: 0.452

Gnomad4 NFE exome AF: 0.402

Gnomad4 OTH exome AF: 0.339

GnomAD4 genome AF: 0.340 AC: 51735 AN: 151994 Hom.: 9425 Cov.: 32 AF XY: 0.339 AC XY: 25190 AN XY: 74280

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.281

Gnomad4 ASJ AF: 0.299

Gnomad4 EAS AF: 0.0745

Gnomad4 SAS AF: 0.245

Gnomad4 FIN AF: 0.449

Gnomad4 NFE AF: 0.396

Gnomad4 OTH AF: 0.316

Alfa AF: 0.373 Hom.: 17641

Bravo AF: 0.323

Asia WGS AF: 0.166 AC: 581 AN: 3478

EpiCase AF: 0.378

EpiControl AF: 0.378

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oculotrichoanal syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.8
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs17219005; hg19: chr9-14770658; COSMIC: COSV66522639;