rs10961689

Variant names:

• chr9-14737508-T-G
• rs10961689
• NM_001379081.2:c.6428A>C

Your query was ambiguous. Multiple possible variants found:

• chr9-14737508-T-G
• chr9-14737508-T-A
• chr9-14737508-T-C

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.6428A>C​(p.Gln2143Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 1,612,218 control chromosomes in the GnomAD database, including 431,661 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42516 hom., cov: 31)
  • Exomes 𝑓: 0.73 (389145 hom.)
• Consequence: FREM1 NM_001379081.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.576
• Publications: 47 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=1.3810069E-6).
• BP6: Variant 9-14737508-T-G is Benign according to our data. Variant chr9-14737508-T-G is described in ClinVar as Benign. ClinVar VariationId is 262545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.779 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.6428A>C	p.Gln2143Pro	missense	Exon 37 of 37	NP_001366010.1	Q5H8C1-1
	FREM1	NM_144966.7		c.6428A>C	p.Gln2143Pro	missense	Exon 38 of 38	NP_659403.4
	FREM1	NM_001177704.3		c.2036A>C	p.Gln679Pro	missense	Exon 14 of 14	NP_001171175.1	Q5H8C1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	ENST00000380880.4	TSL:5 MANE Select	c.6428A>C	p.Gln2143Pro	missense	Exon 37 of 37	ENSP00000370262.3	Q5H8C1-1
	FREM1	ENST00000380894.5	TSL:1	c.2036A>C	p.Gln679Pro	missense	Exon 14 of 14	ENSP00000370278.1	Q5H8C1-2
	FREM1	ENST00000380875.7	TSL:1	n.*994A>C		non_coding_transcript_exon	Exon 31 of 31	ENSP00000370257.3	F8WE85

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113483 AN: 151860 Hom.: 42495 Cov.: 31

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.652

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.752

GnomAD2 exomes AF: 0.735 AC: 181690 AN: 247034 AF XY: 0.731

Gnomad AFR exome AF: 0.790

Gnomad AMR exome AF: 0.753

Gnomad ASJ exome AF: 0.830

Gnomad EAS exome AF: 0.776

Gnomad FIN exome AF: 0.702

Gnomad NFE exome AF: 0.738

Gnomad OTH exome AF: 0.748

GnomAD4 exome AF: 0.729 AC: 1064555 AN: 1460238 Hom.: 389145 Cov.: 43 AF XY: 0.727 AC XY: 528254 AN XY: 726350

African (AFR) AF: 0.787 AC: 26327 AN: 33462

American (AMR) AF: 0.754 AC: 33611 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.829 AC: 21645 AN: 26100

East Asian (EAS) AF: 0.721 AC: 28582 AN: 39656

South Asian (SAS) AF: 0.647 AC: 55717 AN: 86074

European-Finnish (FIN) AF: 0.699 AC: 37277 AN: 53322

Middle Eastern (MID) AF: 0.799 AC: 4605 AN: 5766

European-Non Finnish (NFE) AF: 0.731 AC: 812275 AN: 1110988

Other (OTH) AF: 0.738 AC: 44516 AN: 60318

GnomAD4 genome AF: 0.747 AC: 113560 AN: 151980 Hom.: 42516 Cov.: 31 AF XY: 0.745 AC XY: 55341 AN XY: 74276

African (AFR) AF: 0.786 AC: 32560 AN: 41430

American (AMR) AF: 0.751 AC: 11468 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.827 AC: 2869 AN: 3470

East Asian (EAS) AF: 0.775 AC: 3994 AN: 5154

South Asian (SAS) AF: 0.650 AC: 3123 AN: 4802

European-Finnish (FIN) AF: 0.707 AC: 7460 AN: 10552

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.730 AC: 49618 AN: 67984

Other (OTH) AF: 0.752 AC: 1587 AN: 2110

Alfa AF: 0.739 Hom.: 200619

Bravo AF: 0.756

TwinsUK AF: 0.720 AC: 2670

ALSPAC AF: 0.741 AC: 2854

ESP6500AA AF: 0.793 AC: 3022

ESP6500EA AF: 0.734 AC: 6057

ExAC AF: 0.732 AC: 88386

Asia WGS AF: 0.686 AC: 2385 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	3	Oculotrichoanal syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.9
DANN	Benign	0.78
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0000014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	L
PhyloP100		-0.58
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.016
Sift	Benign	0.31	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.13
ClinPred		0.00098	T
GERP RS		-0.73
Varity_R		0.15
gMVP		0.84
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: rs10961689; hg19: chr9-14737506; COSMIC: COSV66519900;