9-14776147-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001379081.2(FREM1):​c.4499A>G​(p.Glu1500Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,409,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1500V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FREM1 NM_001379081.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32117483).

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>G	p.Glu1500Gly	missense	Exon 25 of 37	NP_001366010.1	Q5H8C1-1
	FREM1	NM_144966.7		c.4499A>G	p.Glu1500Gly	missense	Exon 26 of 38	NP_659403.4
	FREM1	NM_001177704.3		c.107A>G	p.Glu36Gly	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>G	p.Glu1500Gly	missense	Exon 25 of 37	ENSP00000370262.3	Q5H8C1-1
	FREM1	ENST00000380894.5	TSL:1	c.107A>G	p.Glu36Gly	missense	Exon 2 of 14	ENSP00000370278.1	Q5H8C1-2
	FREM1	ENST00000380875.7	TSL:1	n.3981+16596A>G		intron	N/A	ENSP00000370257.3	F8WE85

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000967 AC: 2 AN: 206884 AF XY: 0.0000181

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1409746 Hom.: 0 Cov.: 34 AF XY: 0.00000288 AC XY: 2 AN XY: 695032

African (AFR) AF: 0.00 AC: 0 AN: 32136

American (AMR) AF: 0.00 AC: 0 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: 0.0000130 AC: 1 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: 0.0000172 AC: 1 AN: 58086

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.8
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.13
Sift	Benign	0.087	T
Sift4G	Uncertain	0.020	D
Polyphen		0.92	P
Vest4		0.33
MutPred		0.44		Loss of stability (P = 0.0358)
MVP		0.73
ClinPred		0.76	D
GERP RS		6.0
Varity_R		0.48
gMVP		0.66
Mutation Taster		=22/78	disease causing

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;