rs10738380

Variant names:

• chr9-14801689-T-C
• rs10738380
• NM_001379081.2:c.3657A>G

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.3657A>G​(p.Ala1219Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,613,132 control chromosomes in the GnomAD database, including 41,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1219A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (2961 hom., cov: 33)
  • Exomes 𝑓: 0.23 (38242 hom.)
• Consequence: FREM1 NM_001379081.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.162
• Publications: 18 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=-0.83).
• BP6: Variant 9-14801689-T-C is Benign according to our data. Variant chr9-14801689-T-C is described in ClinVar as Benign. ClinVar VariationId is 262538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.162 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.234 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.3657A>G	p.Ala1219Ala	synonymous	Exon 20 of 37	NP_001366010.1	Q5H8C1-1
	FREM1	NM_144966.7		c.3657A>G	p.Ala1219Ala	synonymous	Exon 21 of 38	NP_659403.4
	FREM1	NR_163238.2		n.4473A>G		non_coding_transcript_exon	Exon 21 of 31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	ENST00000380880.4	TSL:5 MANE Select	c.3657A>G	p.Ala1219Ala	synonymous	Exon 20 of 37	ENSP00000370262.3	Q5H8C1-1
	FREM1	ENST00000380875.7	TSL:1	n.3657A>G		non_coding_transcript_exon	Exon 21 of 31	ENSP00000370257.3	F8WE85
	FREM1	ENST00000895028.1		c.3657A>G	p.Ala1219Ala	synonymous	Exon 20 of 37	ENSP00000565087.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27554 AN: 152076 Hom.: 2962 Cov.: 33

Gnomad AFR AF: 0.0585

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.218 AC: 54349 AN: 249116 AF XY: 0.221

Gnomad AFR exome AF: 0.0557

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.231

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.226 AC: 330683 AN: 1460938 Hom.: 38242 Cov.: 31 AF XY: 0.227 AC XY: 164743 AN XY: 726804

African (AFR) AF: 0.0503 AC: 1683 AN: 33470

American (AMR) AF: 0.213 AC: 9512 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5979 AN: 26132

East Asian (EAS) AF: 0.211 AC: 8380 AN: 39696

South Asian (SAS) AF: 0.241 AC: 20751 AN: 86242

European-Finnish (FIN) AF: 0.223 AC: 11924 AN: 53396

Middle Eastern (MID) AF: 0.139 AC: 799 AN: 5768

European-Non Finnish (NFE) AF: 0.233 AC: 258700 AN: 1111174

Other (OTH) AF: 0.215 AC: 12955 AN: 60352

GnomAD4 genome AF: 0.181 AC: 27553 AN: 152194 Hom.: 2961 Cov.: 33 AF XY: 0.181 AC XY: 13490 AN XY: 74398

African (AFR) AF: 0.0582 AC: 2420 AN: 41548

American (AMR) AF: 0.197 AC: 3008 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 783 AN: 3466

East Asian (EAS) AF: 0.215 AC: 1108 AN: 5164

South Asian (SAS) AF: 0.223 AC: 1076 AN: 4822

European-Finnish (FIN) AF: 0.226 AC: 2395 AN: 10586

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16144 AN: 67990

Other (OTH) AF: 0.188 AC: 397 AN: 2114

Alfa AF: 0.210 Hom.: 10009

Bravo AF: 0.173

Asia WGS AF: 0.217 AC: 755 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)
-	-	1	Oculotrichoanal syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.79
DANN	Benign	0.51
PhyloP100		-0.16
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: rs10738380; hg19: chr9-14801687; COSMIC: COSV66518021;