rs35870000

Variant names:

• chr9-14801712-C-A
• rs35870000
• NM_001379081.2:c.3634G>T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:5
• Conservation: PhyloP100: 0.565
• Publications: 29 publications found

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]

FREM1 Gene-Disease associations (from GenCC):

• oculotrichoanal syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• BNAR syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• isolated trigonocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• trigonocephaly 2

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 262537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379081.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	NM_001379081.2	MANE Select	c.3634G>T	p.Ala1212Ser	missense	Exon 20 of 37	NP_001366010.1	Q5H8C1-1
	FREM1	NM_144966.7		c.3634G>T	p.Ala1212Ser	missense	Exon 21 of 38	NP_659403.4
	FREM1	NR_163238.2		n.4450G>T		non_coding_transcript_exon	Exon 21 of 31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	ENST00000380880.4	TSL:5 MANE Select	c.3634G>T	p.Ala1212Ser	missense	Exon 20 of 37	ENSP00000370262.3	Q5H8C1-1
	FREM1	ENST00000380875.7	TSL:1	n.3634G>T		non_coding_transcript_exon	Exon 21 of 31	ENSP00000370257.3	F8WE85
	FREM1	ENST00000895028.1		c.3634G>T	p.Ala1212Ser	missense	Exon 20 of 37	ENSP00000565087.1

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

GnomAD2 exomes AF: 0.335 AC: 83429 AN: 249200 AF XY: 0.337

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 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

African (AFR) AF: 0.106 AC: 3548 AN: 33476

American (AMR) AF: 0.439 AC: 19654 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 9104 AN: 26128

East Asian (EAS) AF: 0.224 AC: 8912 AN: 39700

South Asian (SAS) AF: 0.337 AC: 29042 AN: 86244

European-Finnish (FIN) AF: 0.327 AC: 17476 AN: 53402

Middle Eastern (MID) AF: 0.322 AC: 1859 AN: 5766

European-Non Finnish (NFE) AF: 0.357 AC: 396827 AN: 1111272

Other (OTH) AF: 0.337 AC: 20313 AN: 60354

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

African (AFR) AF: 0.118 AC: 4913 AN: 41532

American (AMR) AF: 0.374 AC: 5719 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1179 AN: 3468

East Asian (EAS) AF: 0.207 AC: 1071 AN: 5168

South Asian (SAS) AF: 0.346 AC: 1668 AN: 4816

European-Finnish (FIN) AF: 0.325 AC: 3436 AN: 10570

Middle Eastern (MID) AF: 0.360 AC: 105 AN: 292

European-Non Finnish (NFE) AF: 0.354 AC: 24094 AN: 67980

Other (OTH) AF: 0.307 AC: 648 AN: 2110

Alfa AF: 0.327 Hom.: 20058

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Oculotrichoanal syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.56
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.021
Sift	Benign	0.66	T
Sift4G	Benign	0.84	T
Polyphen		0.0030	B
Vest4		0.15
ClinPred		0.0034	T
GERP RS		1.8
Varity_R		0.057
gMVP		0.35
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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