rs35870000

chr9-14801712-C-A

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.3634G>T(p.Ala1212Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,613,200 control chromosomes in the GnomAD database, including 97,219 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 0.28 (7126 hom., cov: 32)
  • Exomes 𝑓: 0.35 (90093 hom.)
• Consequence: FREM1 NM_001379081.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.565

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=0.002292037).
• BP6: Variant 9-14801712-C-A is Benign according to our data. Variant chr9-14801712-C-A is described in ClinVar as [Benign]. Clinvar id is 262537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-14801712-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM1	NM_001379081.2	c.3634G>T	p.Ala1212Ser	missense_variant	20/37	ENST00000380880.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM1	ENST00000380880.4	c.3634G>T	p.Ala1212Ser	missense_variant	20/37	5	NM_001379081.2	P1
FREM1	ENST00000380875.7	c.3634G>T	p.Ala1212Ser	missense_variant, NMD_transcript_variant	21/31	1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43279 AN: 152016 Hom.: 7114 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.349

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.299

GnomAD3 exomes AF: 0.335 AC: 83429 AN: 249200 Hom.: 14863 AF XY: 0.337 AC XY: 45564 AN XY: 135190

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.337

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.353

GnomAD4 exome AF: 0.347 AC: 506735 AN: 1461064 Hom.: 90093 Cov.: 38 AF XY: 0.348 AC XY: 252758 AN XY: 726832

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.439

Gnomad4 ASJ exome AF: 0.348

Gnomad4 EAS exome AF: 0.224

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.327

Gnomad4 NFE exome AF: 0.357

Gnomad4 OTH exome AF: 0.337

GnomAD4 genome AF: 0.285 AC: 43316 AN: 152136 Hom.: 7126 Cov.: 32 AF XY: 0.287 AC XY: 21370 AN XY: 74352

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.374

Gnomad4 ASJ AF: 0.340

Gnomad4 EAS AF: 0.207

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.325

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.307

Alfa AF: 0.339 Hom.: 13913

Bravo AF: 0.282

TwinsUK AF: 0.345 AC: 1279

ALSPAC AF: 0.357 AC: 1375

ESP6500AA AF: 0.119 AC: 472

ESP6500EA AF: 0.338 AC: 2824

ExAC AF: 0.324 AC: 39173

Asia WGS AF: 0.327 AC: 1137 AN: 3478

EpiCase AF: 0.365

EpiControl AF: 0.363

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2020	- -
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

-

- -

Oculotrichoanal syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	6.5
Dann	Benign	0.91
DEOGEN2	Benign	0.044	T;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.71	T;.
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.77	N;N
REVEL	Benign	0.021
Sift	Benign	0.66	T;T
Sift4G	Benign	0.84	T;T
Polyphen		0.0030	B;B
Vest4		0.15
ClinPred		0.0034	T
GERP RS		1.8
Varity_R		0.057
gMVP		0.35

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: rs35870000; hg19: chr9-14801710; COSMIC: COSV66523697;