rs10810249

Variant names:

• chr9-14806850-C-A
• rs10810249
• NM_001379081.2:c.3089-4G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-14806850-C-A
• chr9-14806850-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.3089-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,565,898 control chromosomes in the GnomAD database, including 42,120 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3329 hom., cov: 32)
  • Exomes 𝑓: 0.23 (38791 hom.)
• Consequence: FREM1 NM_001379081.2 splice_region, intron
• Scores: Splicing: ADA: 0.000007089
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.641
• Publications: 12 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 (BayesDel_noAF=-0.52).
• BP6: Variant 9-14806850-C-A is Benign according to our data. Variant chr9-14806850-C-A is described in ClinVar as Benign. ClinVar VariationId is 262536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.245 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.3089-4G>T		splice_region intron	N/A	NP_001366010.1	Q5H8C1-1
	FREM1	NM_144966.7		c.3089-4G>T		splice_region intron	N/A	NP_659403.4
	FREM1	NR_163238.2		n.3905-4G>T		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	ENST00000380880.4	TSL:5 MANE Select	c.3089-4G>T		splice_region intron	N/A	ENSP00000370262.3	Q5H8C1-1
	FREM1	ENST00000380875.7	TSL:1	n.3089-4G>T		splice_region intron	N/A	ENSP00000370257.3	F8WE85
	FREM1	ENST00000895028.1		c.3089-4G>T		splice_region intron	N/A	ENSP00000565087.1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29248 AN: 151998 Hom.: 3329 Cov.: 32

Gnomad AFR AF: 0.0766

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.0882

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.231

GnomAD2 exomes AF: 0.228 AC: 49526 AN: 216886 AF XY: 0.228

Gnomad AFR exome AF: 0.0711

Gnomad AMR exome AF: 0.292

Gnomad ASJ exome AF: 0.274

Gnomad EAS exome AF: 0.0997

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.229 AC: 324234 AN: 1413782 Hom.: 38791 Cov.: 24 AF XY: 0.230 AC XY: 161039 AN XY: 701640

African (AFR) AF: 0.0718 AC: 2320 AN: 32316

American (AMR) AF: 0.282 AC: 11366 AN: 40322

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 6717 AN: 24960

East Asian (EAS) AF: 0.0964 AC: 3768 AN: 39084

South Asian (SAS) AF: 0.219 AC: 17790 AN: 81072

European-Finnish (FIN) AF: 0.242 AC: 12615 AN: 52200

Middle Eastern (MID) AF: 0.311 AC: 1747 AN: 5624

European-Non Finnish (NFE) AF: 0.236 AC: 254916 AN: 1079468

Other (OTH) AF: 0.221 AC: 12995 AN: 58736

GnomAD4 genome AF: 0.192 AC: 29249 AN: 152116 Hom.: 3329 Cov.: 32 AF XY: 0.192 AC XY: 14278 AN XY: 74356

African (AFR) AF: 0.0765 AC: 3177 AN: 41506

American (AMR) AF: 0.252 AC: 3846 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 913 AN: 3470

East Asian (EAS) AF: 0.0882 AC: 456 AN: 5168

South Asian (SAS) AF: 0.197 AC: 953 AN: 4826

European-Finnish (FIN) AF: 0.248 AC: 2626 AN: 10582

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.243 AC: 16528 AN: 67972

Other (OTH) AF: 0.229 AC: 484 AN: 2114

Alfa AF: 0.202 Hom.: 1618

Bravo AF: 0.190

Asia WGS AF: 0.151 AC: 528 AN: 3478

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	-0.52
CADD	Benign	1.2
DANN	Benign	0.36
PhyloP100		-0.64
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000071
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.040		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: rs10810249; hg19: chr9-14806848; COSMIC: COSV66524500;