rs2779500

Variant names:

• chr9-14846038-C-G
• rs2779500
• NM_001379081.2:c.1315G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-14846038-C-G
• chr9-14846038-C-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.1315G>C​(p.Val439Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 1,605,884 control chromosomes in the GnomAD database, including 290,110 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 0.55 (23862 hom., cov: 33)
  • Exomes 𝑓: 0.60 (266248 hom.)
• Consequence: FREM1 NM_001379081.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.30
• Publications: 34 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=3.6315664E-6).
• BP6: Variant 9-14846038-C-G is Benign according to our data. Variant chr9-14846038-C-G is described in ClinVar as Benign. ClinVar VariationId is 262534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.618 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.1315G>C	p.Val439Leu	missense	Exon 8 of 37	NP_001366010.1	Q5H8C1-1
	FREM1	NM_144966.7		c.1315G>C	p.Val439Leu	missense	Exon 9 of 38	NP_659403.4
	FREM1	NR_163238.2		n.2131G>C		non_coding_transcript_exon	Exon 9 of 31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	ENST00000380880.4	TSL:5 MANE Select	c.1315G>C	p.Val439Leu	missense	Exon 8 of 37	ENSP00000370262.3	Q5H8C1-1
	FREM1	ENST00000380875.7	TSL:1	n.1315G>C		non_coding_transcript_exon	Exon 9 of 31	ENSP00000370257.3	F8WE85
	FREM1	ENST00000895028.1		c.1315G>C	p.Val439Leu	missense	Exon 8 of 37	ENSP00000565087.1

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84213 AN: 151968 Hom.: 23857 Cov.: 33

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.626

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.635

Gnomad FIN AF: 0.596

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.544

GnomAD2 exomes AF: 0.557 AC: 132436 AN: 237640 AF XY: 0.570

Gnomad AFR exome AF: 0.474

Gnomad AMR exome AF: 0.426

Gnomad ASJ exome AF: 0.614

Gnomad EAS exome AF: 0.268

Gnomad FIN exome AF: 0.606

Gnomad NFE exome AF: 0.616

Gnomad OTH exome AF: 0.556

GnomAD4 exome AF: 0.601 AC: 873081 AN: 1453798 Hom.: 266248 Cov.: 36 AF XY: 0.603 AC XY: 435673 AN XY: 722526

African (AFR) AF: 0.473 AC: 15776 AN: 33378

American (AMR) AF: 0.435 AC: 19008 AN: 43682

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 15911 AN: 25956

East Asian (EAS) AF: 0.275 AC: 10846 AN: 39416

South Asian (SAS) AF: 0.646 AC: 54866 AN: 84948

European-Finnish (FIN) AF: 0.614 AC: 32539 AN: 53002

Middle Eastern (MID) AF: 0.503 AC: 2895 AN: 5754

European-Non Finnish (NFE) AF: 0.620 AC: 686390 AN: 1107552

Other (OTH) AF: 0.580 AC: 34850 AN: 60110

GnomAD4 genome AF: 0.554 AC: 84238 AN: 152086 Hom.: 23862 Cov.: 33 AF XY: 0.552 AC XY: 41066 AN XY: 74344

African (AFR) AF: 0.480 AC: 19930 AN: 41480

American (AMR) AF: 0.499 AC: 7637 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 2174 AN: 3472

East Asian (EAS) AF: 0.269 AC: 1390 AN: 5172

South Asian (SAS) AF: 0.637 AC: 3068 AN: 4816

European-Finnish (FIN) AF: 0.596 AC: 6292 AN: 10560

Middle Eastern (MID) AF: 0.558 AC: 163 AN: 292

European-Non Finnish (NFE) AF: 0.616 AC: 41899 AN: 67978

Other (OTH) AF: 0.538 AC: 1138 AN: 2114

Alfa AF: 0.575 Hom.: 7018

Bravo AF: 0.538

TwinsUK AF: 0.632 AC: 2343

ALSPAC AF: 0.626 AC: 2413

ESP6500AA AF: 0.487 AC: 2038

ESP6500EA AF: 0.607 AC: 5134

ExAC AF: 0.556 AC: 67235

Asia WGS AF: 0.442 AC: 1542 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Oculotrichoanal syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.7
DANN	Benign	0.86
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.81
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0000036	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.64	N
PhyloP100		1.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.029
Sift	Benign	0.16	T
Sift4G	Benign	0.10	T
Polyphen		0.012	B
Vest4		0.19
ClinPred		0.0035	T
GERP RS		0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.36
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: rs2779500; hg19: chr9-14846036; COSMIC: COSV63087146; COSMIC: COSV63087146;