chr9-14770660-G-T

Variant names:

• chr9-14770660-G-T
• rs17219005
• NM_001379081.2:c.5004C>A

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.5004C>A​(p.Ile1668Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,611,316 control chromosomes in the GnomAD database, including 115,271 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9425 hom., cov: 32)
  • Exomes 𝑓: 0.37 (105846 hom.)
• Consequence: FREM1 NM_001379081.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0310
• Publications: 17 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=-0.57).
• BP6: Variant 9-14770660-G-T is Benign according to our data. Variant chr9-14770660-G-T is described in ClinVar as Benign. ClinVar VariationId is 262543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.031 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 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.5004C>A	p.Ile1668Ile	synonymous	Exon 26 of 37	NP_001366010.1	Q5H8C1-1
	FREM1	NM_144966.7		c.5004C>A	p.Ile1668Ile	synonymous	Exon 27 of 38	NP_659403.4
	FREM1	NM_001177704.3		c.612C>A	p.Ile204Ile	synonymous	Exon 3 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.5004C>A	p.Ile1668Ile	synonymous	Exon 26 of 37	ENSP00000370262.3	Q5H8C1-1
	FREM1	ENST00000380894.5	TSL:1	c.612C>A	p.Ile204Ile	synonymous	Exon 3 of 14	ENSP00000370278.1	Q5H8C1-2
	FREM1	ENST00000380875.7	TSL:1	n.3982-20384C>A		intron	N/A	ENSP00000370257.3	F8WE85

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51703 AN: 151876 Hom.: 9413 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.0745

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.321

GnomAD2 exomes AF: 0.322 AC: 80103 AN: 248932 AF XY: 0.324

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.204

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.0664

Gnomad FIN exome AF: 0.449

Gnomad NFE exome AF: 0.398

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.373 AC: 543891 AN: 1459322 Hom.: 105846 Cov.: 35 AF XY: 0.369 AC XY: 267949 AN XY: 726054

African (AFR) AF: 0.290 AC: 9691 AN: 33438

American (AMR) AF: 0.215 AC: 9618 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 7921 AN: 26110

East Asian (EAS) AF: 0.0805 AC: 3194 AN: 39688

South Asian (SAS) AF: 0.250 AC: 21577 AN: 86208

European-Finnish (FIN) AF: 0.452 AC: 24147 AN: 53382

Middle Eastern (MID) AF: 0.239 AC: 1358 AN: 5688

European-Non Finnish (NFE) AF: 0.402 AC: 445927 AN: 1109796

Other (OTH) AF: 0.339 AC: 20458 AN: 60308

GnomAD4 genome AF: 0.340 AC: 51735 AN: 151994 Hom.: 9425 Cov.: 32 AF XY: 0.339 AC XY: 25190 AN XY: 74280

African (AFR) AF: 0.294 AC: 12201 AN: 41464

American (AMR) AF: 0.281 AC: 4281 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1036 AN: 3468

East Asian (EAS) AF: 0.0745 AC: 386 AN: 5182

South Asian (SAS) AF: 0.245 AC: 1181 AN: 4822

European-Finnish (FIN) AF: 0.449 AC: 4732 AN: 10548

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26888 AN: 67936

Other (OTH) AF: 0.316 AC: 666 AN: 2108

Alfa AF: 0.370 Hom.: 21110

Bravo AF: 0.323

Asia WGS AF: 0.166 AC: 581 AN: 3478

EpiCase AF: 0.378

EpiControl AF: 0.378

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Oculotrichoanal syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.8
DANN	Benign	0.64
PhyloP100		-0.031
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs17219005; hg19: chr9-14770658; COSMIC: COSV66522639;