rs10738377

Variant names:

• chr9-14757746-C-A
• rs10738377
• NM_001379081.2:c.5335-1300G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-14757746-C-A
• chr9-14757746-C-T

Variant summary

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

The NM_001379081.2(FREM1):​c.5335-1300G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 152,164 control chromosomes in the GnomAD database, including 3,278 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 (3278 hom., cov: 32)
• Consequence: FREM1 NM_001379081.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.312
• Publications: 7 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2	c.5335-1300G>T		intron_variant	Intron 28 of 36	ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4	c.5335-1300G>T		intron_variant	Intron 28 of 36	5	NM_001379081.2	ENSP00000370262.3

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28094 AN: 152044 Hom.: 3276 Cov.: 32

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.184

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

GnomAD4 genome AF: 0.185 AC: 28090 AN: 152164 Hom.: 3278 Cov.: 32 AF XY: 0.182 AC XY: 13524 AN XY: 74380

African (AFR) AF: 0.0459 AC: 1906 AN: 41534

American (AMR) AF: 0.137 AC: 2088 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3472

East Asian (EAS) AF: 0.208 AC: 1075 AN: 5174

South Asian (SAS) AF: 0.239 AC: 1153 AN: 4820

European-Finnish (FIN) AF: 0.211 AC: 2235 AN: 10572

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18057 AN: 67982

Other (OTH) AF: 0.182 AC: 385 AN: 2114

Alfa AF: 0.230 Hom.: 14869

Bravo AF: 0.172

Asia WGS AF: 0.215 AC: 750 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.5
DANN	Benign	0.66
PhyloP100		-0.31
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: rs10738377; hg19: chr9-14757744;