rs377670533

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001379081.2(FREM1):c.2169+11A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 1,543,684 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 1 hom. )

Consequence

FREM1
NM_001379081.2 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.0320

Publications

1 publications found

Variant links:

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)

FREM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 9-14824014-T-G is Benign according to our data. Variant chr9-14824014-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 366150.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000493 (75/152220) while in subpopulation NFE AF = 0.00101 (69/68034). AF 95% confidence interval is 0.000821. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FREM1	NM_001379081.2	MANE Select	c.2169+11A>C	intron	N/A	NP_001366010.1
FREM1	NM_144966.7		c.2169+11A>C	intron	N/A	NP_659403.4
FREM1	NR_163238.2		n.2985+11A>C	intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	ENST00000380880.4	TSL:5 MANE Select	c.2169+11A>C		intron	N/A	ENSP00000370262.3
	FREM1	ENST00000380875.7	TSL:1	n.2169+11A>C		intron	N/A	ENSP00000370257.3

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000453

AC:

AN:

202982

AF XY:

0.000479

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000367

Gnomad NFE exome

AF:

0.000930

Gnomad OTH exome

AF:

0.000580

GnomAD4 exome

AF:

0.000360

AC:

501

AN:

1391464

Hom.:

Cov.:

AF XY:

0.000432

AC XY:

298

AN XY:

689180

show subpopulations

African (AFR)

AF:

0.0000311

AC:

AN:

32190

American (AMR)

AF:

0.00

AC:

AN:

39942

Ashkenazi Jewish (ASJ)

AF:

0.0000400

AC:

AN:

25008

East Asian (EAS)

AF:

0.00

AC:

AN:

38426

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78840

European-Finnish (FIN)

AF:

0.000156

AC:

AN:

51352

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.000453

AC:

481

AN:

1062160

Other (OTH)

AF:

0.000138

AC:

AN:

57898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000493

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68034

Other (OTH)

AF:

0.000955

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000789

Hom.:

Bravo

AF:

0.000389

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Oculotrichoanal syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

5.4

(source)

DANN

Benign

0.56

PhyloP100

-0.032

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over