9-14898163-T-G

Variant names:

• chr9-14898163-T-G
• rs10961780
• NM_001379081.2:c.-268+11751A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001379081.2(FREM1):​c.-268+11751A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 152,154 control chromosomes in the GnomAD database, including 3,849 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (3849 hom., cov: 33)
• Consequence: FREM1 NM_001379081.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.604
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.372 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	NM_001379081.2	MANE Select	c.-268+11751A>C		intron	N/A	NP_001366010.1
	FREM1	NM_144966.7		c.-268+11751A>C		intron	N/A	NP_659403.4
	FREM1	NM_001370060.1		c.-268+11751A>C		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.-268+11751A>C		intron	N/A	ENSP00000370262.3
	FREM1	ENST00000380875.7	TSL:1	n.-268+11751A>C		intron	N/A	ENSP00000370257.3

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27553 AN: 152036 Hom.: 3836 Cov.: 33

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0787

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.0765

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0891

Gnomad OTH AF: 0.154

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.181 AC: 27584 AN: 152154 Hom.: 3849 Cov.: 33 AF XY: 0.179 AC XY: 13286 AN XY: 74392

African (AFR) AF: 0.377 AC: 15615 AN: 41452

American (AMR) AF: 0.133 AC: 2031 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0787 AC: 273 AN: 3470

East Asian (EAS) AF: 0.347 AC: 1793 AN: 5172

South Asian (SAS) AF: 0.122 AC: 589 AN: 4828

European-Finnish (FIN) AF: 0.0765 AC: 812 AN: 10610

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0891 AC: 6061 AN: 68008

Other (OTH) AF: 0.152 AC: 322 AN: 2116

Alfa AF: 0.116 Hom.: 6881

Bravo AF: 0.195

Asia WGS AF: 0.217 AC: 753 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.71
PhyloP100		-0.60
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: rs10961780; hg19: chr9-14898161;