dbSNP rs4741426: FREM1:p.Val1953Val (chr9-14747414-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001379081.2(FREM1):c.5859T>C(p.Val1953Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,611,672 control chromosomes in the GnomAD database, including 29,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2034 hom., cov: 32)

Exomes 𝑓: 0.19 ( 27232 hom. )

Consequence

FREM1
NM_001379081.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0300

Publications

18 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: 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

FREM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 9-14747414-A-G is Benign according to our data. Variant chr9-14747414-A-G is described in ClinVar as Benign. ClinVar VariationId is 262544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.03 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FREM1	NM_001379081.2	MANE Select	c.5859T>C	p.Val1953Val	synonymous	Exon 33 of 37	NP_001366010.1	Q5H8C1-1
FREM1	NM_144966.7		c.5859T>C	p.Val1953Val	synonymous	Exon 34 of 38	NP_659403.4
FREM1	NM_001177704.3		c.1467T>C	p.Val489Val	synonymous	Exon 10 of 14	NP_001171175.1	Q5H8C1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FREM1	ENST00000380880.4	TSL:5 MANE Select	c.5859T>C	p.Val1953Val	synonymous	Exon 33 of 37	ENSP00000370262.3	Q5H8C1-1
FREM1	ENST00000380894.5	TSL:1	c.1467T>C	p.Val489Val	synonymous	Exon 10 of 14	ENSP00000370278.1	Q5H8C1-2
FREM1	ENST00000380875.7	TSL:1	n.*425T>C		non_coding_transcript_exon	Exon 27 of 31	ENSP00000370257.3	F8WE85

Frequencies

GnomAD3 genomes

AF:

0.148

AC:

22414

AN:

151896

Hom.:

2035

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0351

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.180

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.192

Gnomad SAS

AF:

0.158

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.197

Gnomad OTH

AF:

0.169

GnomAD2 exomes

AF:

0.174

AC:

43346

AN:

248528

AF XY:

0.174

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.191

Gnomad ASJ exome

AF:

0.149

Gnomad EAS exome

AF:

0.180

Gnomad FIN exome

AF:

0.195

Gnomad NFE exome

AF:

0.189

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.189

AC:

276192

AN:

1459658

Hom.:

27232

Cov.:

AF XY:

0.188

AC XY:

136476

AN XY:

726222

show subpopulations

African (AFR)

AF:

0.0293

AC:

980

AN:

33458

American (AMR)

AF:

0.189

AC:

8428

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.147

AC:

3835

AN:

26114

East Asian (EAS)

AF:

0.219

AC:

8691

AN:

39672

South Asian (SAS)

AF:

0.167

AC:

14369

AN:

86192

European-Finnish (FIN)

AF:

0.196

AC:

10488

AN:

53386

Middle Eastern (MID)

AF:

0.120

AC:

690

AN:

5762

European-Non Finnish (NFE)

AF:

0.196

AC:

217692

AN:

1110126

Other (OTH)

AF:

0.183

AC:

11019

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

9992

19984

29976

39968

49960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7572

15144

22716

30288

37860

<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:

0.147

AC:

22414

AN:

152014

Hom.:

2034

Cov.:

AF XY:

0.147

AC XY:

10907

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.0350

AC:

1453

AN:

41512

American (AMR)

AF:

0.180

AC:

2745

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

492

AN:

3470

East Asian (EAS)

AF:

0.192

AC:

988

AN:

5152

South Asian (SAS)

AF:

0.158

AC:

761

AN:

4808

European-Finnish (FIN)

AF:

0.192

AC:

2023

AN:

10538

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.197

AC:

13401

AN:

67960

Other (OTH)

AF:

0.169

AC:

357

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

946

1893

2839

3786

4732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

244

488

732

976

1220

<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:

0.179

Hom.:

5206

Bravo

AF:

0.142

Asia WGS

AF:

0.186

AC:

651

AN:

3478

EpiCase

AF:

0.179

EpiControl

AF:

0.179

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Oculotrichoanal syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.2

(source)

DANN

Benign

0.63

PhyloP100

0.030

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Computational scores

Splicing

Publications

Other links and lift over