9-14737508-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379081.2(FREM1):c.6428A>C(p.Gln2143Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 1,612,218 control chromosomes in the GnomAD database, including 431,661 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42516 hom., cov: 31)
  • Exomes 𝑓: 0.73 (389145 hom.)
• Consequence: FREM1 NM_001379081.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.576

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3810069E-6).
• BP6: Variant 9-14737508-T-G is Benign according to our data. Variant chr9-14737508-T-G is described in ClinVar as [Benign]. Clinvar id is 262545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14737508-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM1	NM_001379081.2	c.6428A>C	p.Gln2143Pro	missense_variant	37/37	ENST00000380880.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM1	ENST00000380880.4	c.6428A>C	p.Gln2143Pro	missense_variant	37/37	5	NM_001379081.2	P1
FREM1	ENST00000380894.5	c.2036A>C	p.Gln679Pro	missense_variant	14/14	1
FREM1	ENST00000380875.7	c.*994A>C		3_prime_UTR_variant, NMD_transcript_variant	31/31	1
FREM1	ENST00000427623.5	c.*609A>C		3_prime_UTR_variant, NMD_transcript_variant	11/11	5

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113483 AN: 151860 Hom.: 42495 Cov.: 31

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.652

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.752

GnomAD3 exomes AF: 0.735 AC: 181690 AN: 247034 Hom.: 66949 AF XY: 0.731 AC XY: 98028 AN XY: 134044

Gnomad AFR exome AF: 0.790

Gnomad AMR exome AF: 0.753

Gnomad ASJ exome AF: 0.830

Gnomad EAS exome AF: 0.776

Gnomad SAS exome AF: 0.646

Gnomad FIN exome AF: 0.702

Gnomad NFE exome AF: 0.738

Gnomad OTH exome AF: 0.748

GnomAD4 exome AF: 0.729 AC: 1064555 AN: 1460238 Hom.: 389145 Cov.: 43 AF XY: 0.727 AC XY: 528254 AN XY: 726350

Gnomad4 AFR exome AF: 0.787

Gnomad4 AMR exome AF: 0.754

Gnomad4 ASJ exome AF: 0.829

Gnomad4 EAS exome AF: 0.721

Gnomad4 SAS exome AF: 0.647

Gnomad4 FIN exome AF: 0.699

Gnomad4 NFE exome AF: 0.731

Gnomad4 OTH exome AF: 0.738

GnomAD4 genome AF: 0.747 AC: 113560 AN: 151980 Hom.: 42516 Cov.: 31 AF XY: 0.745 AC XY: 55341 AN XY: 74276

Gnomad4 AFR AF: 0.786

Gnomad4 AMR AF: 0.751

Gnomad4 ASJ AF: 0.827

Gnomad4 EAS AF: 0.775

Gnomad4 SAS AF: 0.650

Gnomad4 FIN AF: 0.707

Gnomad4 NFE AF: 0.730

Gnomad4 OTH AF: 0.752

Alfa AF: 0.740 Hom.: 103245

Bravo AF: 0.756

TwinsUK AF: 0.720 AC: 2670

ALSPAC AF: 0.741 AC: 2854

ESP6500AA AF: 0.793 AC: 3022

ESP6500EA AF: 0.734 AC: 6057

ExAC AF: 0.732 AC: 88386

Asia WGS AF: 0.686 AC: 2385 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -

Oculotrichoanal syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	1.9
Dann	Benign	0.78
DEOGEN2	Benign	0.040	T;.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.43	T;T;.
MetaRNN	Benign	0.0000014	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	L;.;L
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.090	N;N;N
REVEL	Benign	0.016
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.13
ClinPred		0.00098	T
GERP RS		-0.73
Varity_R		0.15
gMVP		0.84

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: rs10961689; hg19: chr9-14737506; COSMIC: COSV66519900;