13-38687428-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_207361.6(FREM2):c.84C>G(p.Pro28=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,601,794 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P28P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0012 (7 hom.)
• Consequence: FREM2 NM_207361.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.847

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 13-38687428-C-G is Benign according to our data. Variant chr13-38687428-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 193533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-38687428-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.847 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00329 (502/152374) while in subpopulation AFR AF= 0.00815 (339/41592). AF 95% confidence interval is 0.00744. There are 1 homozygotes in gnomad4. There are 255 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM2	NM_207361.6	c.84C>G	p.Pro28=	synonymous_variant	1/24	ENST00000280481.9
FREM2	XM_017020554.2	c.84C>G	p.Pro28=	synonymous_variant	1/3
FREM2	XR_941571.3	n.352C>G		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM2	ENST00000280481.9	c.84C>G	p.Pro28=	synonymous_variant	1/24	1	NM_207361.6	P1

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152256 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00817

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00503

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00194 AC: 432 AN: 222424 Hom.: 3 AF XY: 0.00186 AC XY: 226 AN XY: 121238

Gnomad AFR exome AF: 0.00937

Gnomad AMR exome AF: 0.00380

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00209

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00121 AC: 1760 AN: 1449420 Hom.: 7 Cov.: 30 AF XY: 0.00125 AC XY: 899 AN XY: 720028

Gnomad4 AFR exome AF: 0.00883

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.0000775

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00206

Gnomad4 FIN exome AF: 0.0000196

Gnomad4 NFE exome AF: 0.000859

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00329 AC: 502 AN: 152374 Hom.: 1 Cov.: 34 AF XY: 0.00342 AC XY: 255 AN XY: 74512

Gnomad4 AFR AF: 0.00815

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.00419

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	FREM2: BP4, BP7 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 12, 2014

- -

Isolated cryptophthalmia;C4540036:Fraser syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 13, 2021

- -

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	-0.73
Cadd	Benign	3.8
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs141718695; hg19: chr13-39261565;