rs281875280

Variant names:

• chr9-14776147-T-A
• rs281875280
• NM_001379081.2:c.4499A>T

Your query was ambiguous. Multiple possible variants found:

• chr9-14776147-T-A
• chr9-14776147-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

The NM_001379081.2(FREM1):​c.4499A>T​(p.Glu1500Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000538 in 1,562,082 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1500D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: FREM1 NM_001379081.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:5 O:1
• Conservation: PhyloP100: 4.82
• Publications: 7 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28445536).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000368 (56/152336) while in subpopulation AMR AF = 0.00287 (44/15306). AF 95% confidence interval is 0.0022. There are 1 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.4499A>T	p.Glu1500Val	missense	Exon 25 of 37	NP_001366010.1	Q5H8C1-1
	FREM1	NM_144966.7		c.4499A>T	p.Glu1500Val	missense	Exon 26 of 38	NP_659403.4
	FREM1	NM_001177704.3		c.107A>T	p.Glu36Val	missense	Exon 2 of 14	NP_001171175.1	Q5H8C1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	ENST00000380880.4	TSL:5 MANE Select	c.4499A>T	p.Glu1500Val	missense	Exon 25 of 37	ENSP00000370262.3	Q5H8C1-1
	FREM1	ENST00000380894.5	TSL:1	c.107A>T	p.Glu36Val	missense	Exon 2 of 14	ENSP00000370278.1	Q5H8C1-2
	FREM1	ENST00000380875.7	TSL:1	n.3981+16596A>T		intron	N/A	ENSP00000370257.3	F8WE85

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.0000290 AC: 6 AN: 206884 AF XY: 0.0000181

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000205

GnomAD4 exome AF: 0.0000199 AC: 28 AN: 1409746 Hom.: 0 Cov.: 34 AF XY: 0.0000158 AC XY: 11 AN XY: 695032

African (AFR) AF: 0.0000311 AC: 1 AN: 32136

American (AMR) AF: 0.000439 AC: 17 AN: 38716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22168

East Asian (EAS) AF: 0.00 AC: 0 AN: 39240

South Asian (SAS) AF: 0.00 AC: 0 AN: 77100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5512

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085650

Other (OTH) AF: 0.000172 AC: 10 AN: 58086

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74496

African (AFR) AF: 0.000144 AC: 6 AN: 41578

American (AMR) AF: 0.00287 AC: 44 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000805

ExAC AF: 0.0000332 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	FREM1-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (2)
-	1	-	not specified (1)
-	1	-	Oculotrichoanal syndrome;C2750433:BNAR syndrome;C3280974:Trigonocephaly 2 (1)
1	-	-	Trigonocephaly 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.8
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.21
Sift	Benign	0.065	T
Sift4G	Uncertain	0.013	D
Polyphen		0.86	P
Vest4		0.63
MVP		0.64
ClinPred		0.51	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.59
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs281875280; hg19: chr9-14776145;