13-38690553-T-C

Variant names:

• chr13-38690553-T-C
• rs2496425
• NM_207361.6:c.3209T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207361.6(FREM2):​c.3209T>C​(p.Phe1070Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,613,692 control chromosomes in the GnomAD database, including 84,064 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (17096 hom., cov: 33)
  • Exomes 𝑓: 0.29 (66968 hom.)
• Consequence: FREM2 NM_207361.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.679
• Publications: 37 publications found

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]

FREM2 Gene-Disease associations (from GenCC):

• Fraser syndrome 2

  Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
• Fraser syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fraser syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4487134E-6).
• BP6: Variant 13-38690553-T-C is Benign according to our data. Variant chr13-38690553-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207361.6. 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
	FREM2	NM_207361.6	MANE Select	c.3209T>C	p.Phe1070Ser	missense	Exon 1 of 24	NP_997244.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM2	ENST00000280481.9	TSL:1 MANE Select	c.3209T>C	p.Phe1070Ser	missense	Exon 1 of 24	ENSP00000280481.7

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64680 AN: 152008 Hom.: 17039 Cov.: 33

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.376

GnomAD2 exomes AF: 0.342 AC: 85988 AN: 251426 AF XY: 0.326

Gnomad AFR exome AF: 0.763

Gnomad AMR exome AF: 0.435

Gnomad ASJ exome AF: 0.318

Gnomad EAS exome AF: 0.399

Gnomad FIN exome AF: 0.314

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.322

GnomAD4 exome AF: 0.291 AC: 424958 AN: 1461566 Hom.: 66968 Cov.: 40 AF XY: 0.288 AC XY: 209697 AN XY: 727080

African (AFR) AF: 0.764 AC: 25564 AN: 33476

American (AMR) AF: 0.431 AC: 19278 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 8238 AN: 26134

East Asian (EAS) AF: 0.384 AC: 15257 AN: 39700

South Asian (SAS) AF: 0.295 AC: 25405 AN: 86248

European-Finnish (FIN) AF: 0.316 AC: 16863 AN: 53372

Middle Eastern (MID) AF: 0.273 AC: 1572 AN: 5768

European-Non Finnish (NFE) AF: 0.264 AC: 293584 AN: 1111766

Other (OTH) AF: 0.318 AC: 19197 AN: 60378

GnomAD4 genome AF: 0.426 AC: 64795 AN: 152126 Hom.: 17096 Cov.: 33 AF XY: 0.425 AC XY: 31634 AN XY: 74354

African (AFR) AF: 0.752 AC: 31212 AN: 41490

American (AMR) AF: 0.419 AC: 6409 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1063 AN: 3466

East Asian (EAS) AF: 0.415 AC: 2144 AN: 5166

South Asian (SAS) AF: 0.298 AC: 1440 AN: 4832

European-Finnish (FIN) AF: 0.316 AC: 3346 AN: 10578

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18044 AN: 67988

Other (OTH) AF: 0.375 AC: 793 AN: 2112

Alfa AF: 0.322 Hom.: 32244

Bravo AF: 0.447

TwinsUK AF: 0.265 AC: 984

ALSPAC AF: 0.262 AC: 1011

ESP6500AA AF: 0.752 AC: 3315

ESP6500EA AF: 0.274 AC: 2360

ExAC AF: 0.347 AC: 42146

Asia WGS AF: 0.401 AC: 1396 AN: 3478

EpiCase AF: 0.267

EpiControl AF: 0.268

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Fraser syndrome 2 (2)
-	-	2	not specified (2)
-	-	1	Fraser syndrome 1 (1)
-	-	1	Isolated cryptophthalmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.58
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.037	N
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.68
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.60	N
REVEL	Benign	0.097
Sift	Benign	0.67	T
Sift4G	Benign	0.55	T
Vest4		0.014
MPC		0.21
ClinPred		0.0024	T
GERP RS		6.1
gMVP		0.33
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: rs2496425; hg19: chr13-39264690; COSMIC: COSV54839269;