9-14737194-C-G

Variant names:

• chr9-14737194-C-G
• rs376485630
• NM_001379081.2:c.*202G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_001379081.2(FREM1):​c.*202G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 499,448 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (1 hom.)
• Consequence: FREM1 NM_001379081.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.234
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-14737194-C-G is Benign according to our data. Variant chr9-14737194-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 914604.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00178 (271/152194) while in subpopulation NFE AF = 0.00335 (228/67994). AF 95% confidence interval is 0.003. There are 0 homozygotes in GnomAd4. There are 147 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	NM_001379081.2	MANE Select	c.*202G>C		3_prime_UTR	Exon 37 of 37	NP_001366010.1	Q5H8C1-1
	FREM1	NM_144966.7		c.*202G>C		3_prime_UTR	Exon 38 of 38	NP_659403.4
	FREM1	NM_001177704.3		c.*202G>C		3_prime_UTR	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.*202G>C		3_prime_UTR	Exon 37 of 37	ENSP00000370262.3	Q5H8C1-1
	FREM1	ENST00000380894.5	TSL:1	c.*202G>C		3_prime_UTR	Exon 14 of 14	ENSP00000370278.1	Q5H8C1-2
	FREM1	ENST00000895028.1		c.*202G>C		3_prime_UTR	Exon 37 of 37	ENSP00000565087.1

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000567

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00177 AC: 613 AN: 347254 Hom.: 1 Cov.: 3 AF XY: 0.00167 AC XY: 301 AN XY: 179882

African (AFR) AF: 0.000503 AC: 5 AN: 9934

American (AMR) AF: 0.000156 AC: 2 AN: 12788

Ashkenazi Jewish (ASJ) AF: 0.000172 AC: 2 AN: 11642

East Asian (EAS) AF: 0.00 AC: 0 AN: 26258

South Asian (SAS) AF: 0.00 AC: 0 AN: 21966

European-Finnish (FIN) AF: 0.000797 AC: 19 AN: 23840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1622

European-Non Finnish (NFE) AF: 0.00259 AC: 563 AN: 217788

Other (OTH) AF: 0.00103 AC: 22 AN: 21416

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.00198 AC XY: 147 AN XY: 74406

African (AFR) AF: 0.000626 AC: 26 AN: 41536

American (AMR) AF: 0.000262 AC: 4 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.000567 AC: 6 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00335 AC: 228 AN: 67994

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.00145

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Oculotrichoanal syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.68
DANN	Benign	0.61
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism

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: rs376485630; hg19: chr9-14737192; COSMIC: COSV66529089; COSMIC: COSV66529089;