chr9-14775919-T-A

Variant names:

• chr9-14775919-T-A
• rs2101770
• NM_001379081.2:c.4727A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144966.7(FREM1):​c.4727A>T​(p.Asn1576Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,613,978 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (25 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (72 hom.)
• Consequence: FREM1 NM_144966.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.835
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00500378).
• BP6: Variant 9-14775919-T-A is Benign according to our data. Variant chr9-14775919-T-A is described in ClinVar as Benign. ClinVar VariationId is 262540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00613 (934/152280) while in subpopulation AMR AF = 0.0434 (664/15298). AF 95% confidence interval is 0.0407. There are 25 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144966.7. 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.4727A>T	p.Asn1576Ile	missense	Exon 25 of 37	NP_001366010.1
	FREM1	NM_144966.7		c.4727A>T	p.Asn1576Ile	missense	Exon 26 of 38	NP_659403.4
	FREM1	NM_001177704.3		c.335A>T	p.Asn112Ile	missense	Exon 2 of 14	NP_001171175.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	ENST00000380880.4	TSL:5 MANE Select	c.4727A>T	p.Asn1576Ile	missense	Exon 25 of 37	ENSP00000370262.3
	FREM1	ENST00000380894.5	TSL:1	c.335A>T	p.Asn112Ile	missense	Exon 2 of 14	ENSP00000370278.1
	FREM1	ENST00000380875.7	TSL:1	n.3981+16824A>T		intron	N/A	ENSP00000370257.3

Frequencies

GnomAD3 genomes AF: 0.00612 AC: 931 AN: 152162 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0434

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00298

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00928 AC: 2311 AN: 249070 AF XY: 0.00735

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.0523

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00122

Gnomad FIN exome AF: 0.000510

Gnomad NFE exome AF: 0.00297

Gnomad OTH exome AF: 0.00612

GnomAD4 exome AF: 0.00396 AC: 5784 AN: 1461698 Hom.: 72 Cov.: 37 AF XY: 0.00367 AC XY: 2666 AN XY: 727128

African (AFR) AF: 0.000747 AC: 25 AN: 33478

American (AMR) AF: 0.0491 AC: 2197 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.00307 AC: 122 AN: 39700

South Asian (SAS) AF: 0.00305 AC: 263 AN: 86258

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00268 AC: 2985 AN: 1111858

Other (OTH) AF: 0.00267 AC: 161 AN: 60374

GnomAD4 genome AF: 0.00613 AC: 934 AN: 152280 Hom.: 25 Cov.: 33 AF XY: 0.00717 AC XY: 534 AN XY: 74450

African (AFR) AF: 0.000409 AC: 17 AN: 41564

American (AMR) AF: 0.0434 AC: 664 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5162

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00298 AC: 203 AN: 68026

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00315 Hom.: 1

Bravo AF: 0.00800

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00124 AC: 5

ESP6500EA AF: 0.00274 AC: 23

ExAC AF: 0.00705 AC: 853

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00267

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Oculotrichoanal syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.85
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.83
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.053
Sift	Benign	0.17	T
Sift4G	Benign	0.087	T
Polyphen		0.17	B
Vest4		0.30
MVP		0.11
ClinPred		0.0074	T
GERP RS		-5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.36
Mutation Taster		=98/2	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: rs2101770; hg19: chr9-14775917;