9-14851619-T-C

Variant names:

• chr9-14851619-T-C
• rs2818940
• NM_001379081.2:c.829-12A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000380880.4(FREM1):​c.829-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 1,590,922 control chromosomes in the GnomAD database, including 507,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42656 hom., cov: 31)
  • Exomes 𝑓: 0.80 (465066 hom.)
• Consequence: FREM1 ENST00000380880.4 intron
• Scores: Splicing: ADA: 0.00001803
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0320
• Publications: 13 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• BNAR syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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, NO_KNOWN Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-14851619-T-C is Benign according to our data. Variant chr9-14851619-T-C is described in ClinVar as Benign. ClinVar VariationId is 262546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000380880.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	NM_001379081.2	MANE Select	c.829-12A>G		intron	N/A	NP_001366010.1
	FREM1	NM_144966.7		c.829-12A>G		intron	N/A	NP_659403.4
	FREM1	NM_001370060.1		c.856-12A>G		intron	N/A	NP_001356989.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	ENST00000380880.4	TSL:5 MANE Select	c.829-12A>G		intron	N/A	ENSP00000370262.3
	FREM1	ENST00000380875.7	TSL:1	n.829-12A>G		intron	N/A	ENSP00000370257.3

Frequencies

GnomAD3 genomes AF: 0.739 AC: 112241 AN: 151930 Hom.: 42632 Cov.: 31

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.778

Gnomad ASJ AF: 0.823

Gnomad EAS AF: 0.962

Gnomad SAS AF: 0.861

Gnomad FIN AF: 0.869

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.757

GnomAD2 exomes AF: 0.809 AC: 200598 AN: 247918 AF XY: 0.815

Gnomad AFR exome AF: 0.533

Gnomad AMR exome AF: 0.798

Gnomad ASJ exome AF: 0.825

Gnomad EAS exome AF: 0.965

Gnomad FIN exome AF: 0.863

Gnomad NFE exome AF: 0.798

Gnomad OTH exome AF: 0.801

GnomAD4 exome AF: 0.802 AC: 1154022 AN: 1438874 Hom.: 465066 Cov.: 27 AF XY: 0.805 AC XY: 577443 AN XY: 717470

African (AFR) AF: 0.544 AC: 17884 AN: 32872

American (AMR) AF: 0.797 AC: 35599 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.826 AC: 21473 AN: 26008

East Asian (EAS) AF: 0.964 AC: 38163 AN: 39580

South Asian (SAS) AF: 0.867 AC: 74438 AN: 85836

European-Finnish (FIN) AF: 0.860 AC: 45849 AN: 53342

Middle Eastern (MID) AF: 0.717 AC: 4096 AN: 5716

European-Non Finnish (NFE) AF: 0.796 AC: 868844 AN: 1091182

Other (OTH) AF: 0.799 AC: 47676 AN: 59648

GnomAD4 genome AF: 0.739 AC: 112314 AN: 152048 Hom.: 42656 Cov.: 31 AF XY: 0.747 AC XY: 55511 AN XY: 74352

African (AFR) AF: 0.545 AC: 22563 AN: 41408

American (AMR) AF: 0.778 AC: 11875 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 2855 AN: 3468

East Asian (EAS) AF: 0.962 AC: 4975 AN: 5172

South Asian (SAS) AF: 0.862 AC: 4154 AN: 4820

European-Finnish (FIN) AF: 0.869 AC: 9203 AN: 10590

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.798 AC: 54274 AN: 68006

Other (OTH) AF: 0.760 AC: 1604 AN: 2110

Alfa AF: 0.778 Hom.: 68533

Bravo AF: 0.722

Asia WGS AF: 0.872 AC: 3036 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.81
CADD	Benign	15
DANN	Benign	0.44
PhyloP100		-0.032
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.13		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: rs2818940; hg19: chr9-14851617;