chr9-14737424-T-C

Variant names:

• chr9-14737424-T-C
• NM_001379081.2:c.6512A>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.6512A>G​(p.His2171Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FREM1 NM_001379081.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.99
• Publications: 0 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=0.30383202).

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.6512A>G	p.His2171Arg	missense	Exon 37 of 37	NP_001366010.1	Q5H8C1-1
	FREM1	NM_144966.7		c.6512A>G	p.His2171Arg	missense	Exon 38 of 38	NP_659403.4
	FREM1	NM_001177704.3		c.2120A>G	p.His707Arg	missense	Exon 14 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.6512A>G	p.His2171Arg	missense	Exon 37 of 37	ENSP00000370262.3	Q5H8C1-1
	FREM1	ENST00000380894.5	TSL:1	c.2120A>G	p.His707Arg	missense	Exon 14 of 14	ENSP00000370278.1	Q5H8C1-2
	FREM1	ENST00000380875.7	TSL:1	n.*1078A>G		non_coding_transcript_exon	Exon 31 of 31	ENSP00000370257.3	F8WE85

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.079
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.0
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.19
Sift	Uncertain	0.022	D
Sift4G	Benign	0.23	T
Polyphen		0.25	B
Vest4		0.33
MutPred		0.52		Gain of phosphorylation at S2176 (P = 0.0787)
MVP		0.31
ClinPred		0.83	D
GERP RS		5.8
Varity_R		0.33
gMVP		0.65
Mutation Taster		=57/43	polymorphism

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

hg19: chr9-14737422;