13-38687163-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_207361.6(FREM2):c.-182G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00897 in 793,908 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0081 (24 hom., cov: 34)
  • Exomes 𝑓: 0.0092 (56 hom.)
• Consequence: FREM2 NM_207361.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.38

Genes affected

FREM2 (HGNC:25396): (FRAS1 related extracellular matrix 2) This gene encodes an integral membrane protein containing numerous CSPG (chondroitin sulfate proteoglycan element) repeats and Calx-beta domains. The encoded protein localizes to the basement membrane, forming a ternary complex that plays a role in epidermal-dermal interactions. This protein is important for the integrity of skin and renal epithelia. Mutations in this gene are associated with Fraser syndrome. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 13-38687163-G-A is Benign according to our data. Variant chr13-38687163-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 311932.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00813 (1238/152312) while in subpopulation NFE AF= 0.00961 (654/68026). AF 95% confidence interval is 0.009. There are 24 homozygotes in gnomad4. There are 721 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM2	NM_207361.6	c.-182G>A		5_prime_UTR_variant	1/24	ENST00000280481.9
FREM2	XM_017020554.2	c.-182G>A		5_prime_UTR_variant	1/3
FREM2	XR_941571.3	n.87G>A		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM2	ENST00000280481.9	c.-182G>A		5_prime_UTR_variant	1/24	1	NM_207361.6	P1

Frequencies

GnomAD3 genomes AF: 0.00814 AC: 1239 AN: 152194 Hom.: 24 Cov.: 34

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00961

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00917 AC: 5886 AN: 641596 Hom.: 56 Cov.: 9 AF XY: 0.00858 AC XY: 2817 AN XY: 328350

Gnomad4 AFR exome AF: 0.00106

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.000725

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000198

Gnomad4 FIN exome AF: 0.0439

Gnomad4 NFE exome AF: 0.00935

Gnomad4 OTH exome AF: 0.00682

GnomAD4 genome AF: 0.00813 AC: 1238 AN: 152312 Hom.: 24 Cov.: 34 AF XY: 0.00968 AC XY: 721 AN XY: 74488

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0475

Gnomad4 NFE AF: 0.00961

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00352 Hom.: 0

Bravo AF: 0.00472

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fraser syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	2.6
Dann	Benign	0.96

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

LitVar

Other links and lift over

dbSNP: rs142232936; hg19: chr13-39261300;