9-14859358-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.456A>G(p.Gln152=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,613,536 control chromosomes in the GnomAD database, including 29,942 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3139 hom., cov: 32)
  • Exomes 𝑓: 0.17 (26803 hom.)
• Consequence: FREM1 NM_001379081.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0370

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=-0.85).
• BP6: Variant 9-14859358-T-C is Benign according to our data. Variant chr9-14859358-T-C is described in ClinVar as [Benign]. Clinvar id is 366172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14859358-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.037 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM1	NM_001379081.2	c.456A>G	p.Gln152=	synonymous_variant	4/37	ENST00000380880.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM1	ENST00000380880.4	c.456A>G	p.Gln152=	synonymous_variant	4/37	5	NM_001379081.2	P1
FREM1	ENST00000380875.7	c.456A>G	p.Gln152=	synonymous_variant, NMD_transcript_variant	5/31	1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27909 AN: 151924 Hom.: 3136 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.177

GnomAD3 exomes AF: 0.218 AC: 54438 AN: 249218 Hom.: 7690 AF XY: 0.210 AC XY: 28365 AN XY: 135202

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.337

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.557

Gnomad SAS exome AF: 0.170

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.175 AC: 255347 AN: 1461494 Hom.: 26803 Cov.: 33 AF XY: 0.173 AC XY: 125998 AN XY: 727034

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.325

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.573

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.226

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.184 AC: 27927 AN: 152042 Hom.: 3139 Cov.: 32 AF XY: 0.192 AC XY: 14301 AN XY: 74298

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.260

Gnomad4 ASJ AF: 0.180

Gnomad4 EAS AF: 0.555

Gnomad4 SAS AF: 0.175

Gnomad4 FIN AF: 0.244

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.178

Alfa AF: 0.157 Hom.: 1012

Bravo AF: 0.190

Asia WGS AF: 0.297 AC: 1033 AN: 3478

EpiCase AF: 0.159

EpiControl AF: 0.148

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

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	-0.85
Cadd	Benign	2.3
Dann	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs10961757; hg19: chr9-14859356; COSMIC: COSV66523705;