chr9-14801689-T-C

Position:

• chr9-14801689-T-C

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.3657A>G​(p.Ala1219=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,613,132 control chromosomes in the GnomAD database, including 41,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2961 hom., cov: 33)
  • Exomes 𝑓: 0.23 (38242 hom.)
• Consequence: FREM1 NM_001379081.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.162

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=-0.83).
• BP6: Variant 9-14801689-T-C is Benign according to our data. Variant chr9-14801689-T-C is described in ClinVar as [Benign]. Clinvar id is 262538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14801689-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.162 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FREM1	NM_001379081.2	c.3657A>G	p.Ala1219=	synonymous_variant	20/37	ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4	c.3657A>G	p.Ala1219=	synonymous_variant	20/37	5	NM_001379081.2	ENSP00000370262	P1
FREM1	ENST00000380875.7	c.3657A>G	p.Ala1219=	synonymous_variant, NMD_transcript_variant	21/31	1		ENSP00000370257

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27554 AN: 152076 Hom.: 2962 Cov.: 33

Gnomad AFR AF: 0.0585

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.190

GnomAD3 exomes AF: 0.218 AC: 54349 AN: 249116 Hom.: 6198 AF XY: 0.221 AC XY: 29805 AN XY: 135144

Gnomad AFR exome AF: 0.0557

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.231

Gnomad SAS exome AF: 0.240

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.226 AC: 330683 AN: 1460938 Hom.: 38242 Cov.: 31 AF XY: 0.227 AC XY: 164743 AN XY: 726804

Gnomad4 AFR exome AF: 0.0503

Gnomad4 AMR exome AF: 0.213

Gnomad4 ASJ exome AF: 0.229

Gnomad4 EAS exome AF: 0.211

Gnomad4 SAS exome AF: 0.241

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.181 AC: 27553 AN: 152194 Hom.: 2961 Cov.: 33 AF XY: 0.181 AC XY: 13490 AN XY: 74398

Gnomad4 AFR AF: 0.0582

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.226

Gnomad4 EAS AF: 0.215

Gnomad4 SAS AF: 0.223

Gnomad4 FIN AF: 0.226

Gnomad4 NFE AF: 0.237

Gnomad4 OTH AF: 0.188

Alfa AF: 0.222 Hom.: 7501

Bravo AF: 0.173

Asia WGS AF: 0.217 AC: 755 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2020	- -

Oculotrichoanal syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.79
DANN	Benign	0.51

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: rs10738380; hg19: chr9-14801687; COSMIC: COSV66518021;