9-14819372-G-T

Variant names:

• chr9-14819372-G-T
• rs7023244
• NM_001379081.2:c.2408C>A

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.2408C>A​(p.Ser803Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,612,312 control chromosomes in the GnomAD database, including 44,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S803F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.20 (3471 hom., cov: 33)
  • Exomes 𝑓: 0.23 (41008 hom.)
• Consequence: FREM1 NM_001379081.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 8.51
• Publications: 32 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 (MetaRNN=0.0020454526).
• BP6: Variant 9-14819372-G-T is Benign according to our data. Variant chr9-14819372-G-T is described in ClinVar as Benign. ClinVar VariationId is 262535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.248 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.2408C>A	p.Ser803Tyr	missense	Exon 14 of 37	NP_001366010.1	Q5H8C1-1
	FREM1	NM_144966.7		c.2408C>A	p.Ser803Tyr	missense	Exon 15 of 38	NP_659403.4
	FREM1	NR_163238.2		n.3224C>A		non_coding_transcript_exon	Exon 15 of 31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	ENST00000380880.4	TSL:5 MANE Select	c.2408C>A	p.Ser803Tyr	missense	Exon 14 of 37	ENSP00000370262.3	Q5H8C1-1
	FREM1	ENST00000380875.7	TSL:1	n.2408C>A		non_coding_transcript_exon	Exon 15 of 31	ENSP00000370257.3	F8WE85
	FREM1	ENST00000895028.1		c.2408C>A	p.Ser803Tyr	missense	Exon 14 of 37	ENSP00000565087.1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30703 AN: 152086 Hom.: 3472 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.0893

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.231 AC: 57314 AN: 248550 AF XY: 0.230

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.290

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.0973

Gnomad FIN exome AF: 0.241

Gnomad NFE exome AF: 0.247

Gnomad OTH exome AF: 0.239

GnomAD4 exome AF: 0.233 AC: 340296 AN: 1460108 Hom.: 41008 Cov.: 32 AF XY: 0.233 AC XY: 169321 AN XY: 726396

African (AFR) AF: 0.109 AC: 3640 AN: 33468

American (AMR) AF: 0.283 AC: 12648 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 7052 AN: 26110

East Asian (EAS) AF: 0.0948 AC: 3762 AN: 39680

South Asian (SAS) AF: 0.223 AC: 19207 AN: 86180

European-Finnish (FIN) AF: 0.238 AC: 12699 AN: 53364

Middle Eastern (MID) AF: 0.316 AC: 1821 AN: 5766

European-Non Finnish (NFE) AF: 0.239 AC: 265821 AN: 1110562

Other (OTH) AF: 0.226 AC: 13646 AN: 60332

GnomAD4 genome AF: 0.202 AC: 30704 AN: 152204 Hom.: 3471 Cov.: 33 AF XY: 0.201 AC XY: 14962 AN XY: 74400

African (AFR) AF: 0.110 AC: 4585 AN: 41556

American (AMR) AF: 0.254 AC: 3890 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 911 AN: 3466

East Asian (EAS) AF: 0.0894 AC: 462 AN: 5170

South Asian (SAS) AF: 0.201 AC: 969 AN: 4818

European-Finnish (FIN) AF: 0.244 AC: 2590 AN: 10596

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.243 AC: 16530 AN: 67996

Other (OTH) AF: 0.237 AC: 500 AN: 2110

Alfa AF: 0.227 Hom.: 18244

Bravo AF: 0.200

TwinsUK AF: 0.248 AC: 920

ALSPAC AF: 0.245 AC: 943

ESP6500AA AF: 0.117 AC: 455

ESP6500EA AF: 0.247 AC: 2046

ExAC AF: 0.229 AC: 27633

Asia WGS AF: 0.160 AC: 558 AN: 3478

EpiCase AF: 0.242

EpiControl AF: 0.247

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		8.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.34
Sift	Benign	0.043	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.56
ClinPred		0.038	T
GERP RS		5.9
Varity_R		0.45
gMVP		0.65
Mutation Taster		=97/3	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: rs7023244; hg19: chr9-14819370; COSMIC: COSV66524510;