9-14775861-G-A

Variant names:

• chr9-14775861-G-A
• rs10733289
• NM_001379081.2:c.4785C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001379081.2(FREM1):​c.4785C>T​(p.Ala1595Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,612,504 control chromosomes in the GnomAD database, including 249,104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18981 hom., cov: 32)
  • Exomes 𝑓: 0.56 (230123 hom.)
• Consequence: FREM1 NM_001379081.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.642
• Publications: 28 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 9-14775861-G-A is Benign according to our data. Variant chr9-14775861-G-A is described in ClinVar as Benign. ClinVar VariationId is 262541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.642 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.579 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.4785C>T	p.Ala1595Ala	synonymous	Exon 25 of 37	NP_001366010.1	Q5H8C1-1
	FREM1	NM_144966.7		c.4785C>T	p.Ala1595Ala	synonymous	Exon 26 of 38	NP_659403.4
	FREM1	NM_001177704.3		c.393C>T	p.Ala131Ala	synonymous	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.4785C>T	p.Ala1595Ala	synonymous	Exon 25 of 37	ENSP00000370262.3	Q5H8C1-1
	FREM1	ENST00000380894.5	TSL:1	c.393C>T	p.Ala131Ala	synonymous	Exon 2 of 14	ENSP00000370278.1	Q5H8C1-2
	FREM1	ENST00000380875.7	TSL:1	n.3981+16882C>T		intron	N/A	ENSP00000370257.3	F8WE85

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73660 AN: 151880 Hom.: 18967 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.476

GnomAD2 exomes AF: 0.506 AC: 126023 AN: 249074 AF XY: 0.511

Gnomad AFR exome AF: 0.332

Gnomad AMR exome AF: 0.380

Gnomad ASJ exome AF: 0.505

Gnomad EAS exome AF: 0.321

Gnomad FIN exome AF: 0.626

Gnomad NFE exome AF: 0.580

Gnomad OTH exome AF: 0.509

GnomAD4 exome AF: 0.556 AC: 811472 AN: 1460506 Hom.: 230123 Cov.: 46 AF XY: 0.553 AC XY: 402145 AN XY: 726564

African (AFR) AF: 0.324 AC: 10855 AN: 33462

American (AMR) AF: 0.390 AC: 17459 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 13160 AN: 26134

East Asian (EAS) AF: 0.297 AC: 11769 AN: 39692

South Asian (SAS) AF: 0.485 AC: 41804 AN: 86242

European-Finnish (FIN) AF: 0.627 AC: 33476 AN: 53402

Middle Eastern (MID) AF: 0.391 AC: 2256 AN: 5766

European-Non Finnish (NFE) AF: 0.585 AC: 649266 AN: 1110762

Other (OTH) AF: 0.521 AC: 31427 AN: 60328

GnomAD4 genome AF: 0.485 AC: 73694 AN: 151998 Hom.: 18981 Cov.: 32 AF XY: 0.484 AC XY: 35957 AN XY: 74308

African (AFR) AF: 0.333 AC: 13791 AN: 41442

American (AMR) AF: 0.428 AC: 6550 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1731 AN: 3472

East Asian (EAS) AF: 0.313 AC: 1617 AN: 5172

South Asian (SAS) AF: 0.467 AC: 2248 AN: 4814

European-Finnish (FIN) AF: 0.622 AC: 6560 AN: 10554

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.584 AC: 39674 AN: 67950

Other (OTH) AF: 0.471 AC: 991 AN: 2106

Alfa AF: 0.528 Hom.: 37573

Bravo AF: 0.459

Asia WGS AF: 0.386 AC: 1347 AN: 3478

EpiCase AF: 0.561

EpiControl AF: 0.562

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.3
DANN	Benign	0.46
PhyloP100		0.64
Mutation Taster		=100/0	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: rs10733289; hg19: chr9-14775859; COSMIC: COSV66519919; COSMIC: COSV66519919;