rs1868463

Variant names:

• chr13-38692347-G-A
• rs1868463
• NM_207361.6:c.5003G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-38692347-G-A
• chr13-38692347-G-C
• chr13-38692347-G-T

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.5003G>A​(p.Arg1668His) variant causes a missense change. The variant allele was found at a frequency of 0.0623 in 1,603,678 control chromosomes in the GnomAD database, including 5,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (434 hom., cov: 32)
  • Exomes 𝑓: 0.063 (4767 hom.)
• Consequence: FREM2 NM_207361.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.93
• Publications: 20 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=0.001679182).
• BP6: Variant 13-38692347-G-A is Benign according to our data. Variant chr13-38692347-G-A is described in ClinVar as Benign. ClinVar VariationId is 193534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.227 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.5003G>A	p.Arg1668His	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.5003G>A	p.Arg1668His	missense	Exon 1 of 24	ENSP00000280481.7	Q5SZK8-1

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9115 AN: 152028 Hom.: 433 Cov.: 32

Gnomad AFR AF: 0.0437

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0589

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.0479

Gnomad OTH AF: 0.0809

GnomAD2 exomes AF: 0.0786 AC: 19187 AN: 244034 AF XY: 0.0844

Gnomad AFR exome AF: 0.0434

Gnomad AMR exome AF: 0.0366

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.235

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.0505

Gnomad OTH exome AF: 0.0756

GnomAD4 exome AF: 0.0625 AC: 90777 AN: 1451532 Hom.: 4767 Cov.: 34 AF XY: 0.0666 AC XY: 48029 AN XY: 720976

African (AFR) AF: 0.0486 AC: 1605 AN: 33052

American (AMR) AF: 0.0391 AC: 1710 AN: 43768

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3603 AN: 25360

East Asian (EAS) AF: 0.262 AC: 10388 AN: 39580

South Asian (SAS) AF: 0.175 AC: 14863 AN: 84852

European-Finnish (FIN) AF: 0.0193 AC: 1026 AN: 53066

Middle Eastern (MID) AF: 0.167 AC: 951 AN: 5694

European-Non Finnish (NFE) AF: 0.0469 AC: 51943 AN: 1106350

Other (OTH) AF: 0.0784 AC: 4688 AN: 59810

GnomAD4 genome AF: 0.0599 AC: 9118 AN: 152146 Hom.: 434 Cov.: 32 AF XY: 0.0621 AC XY: 4621 AN XY: 74356

African (AFR) AF: 0.0436 AC: 1808 AN: 41510

American (AMR) AF: 0.0589 AC: 900 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 494 AN: 3472

East Asian (EAS) AF: 0.239 AC: 1228 AN: 5148

South Asian (SAS) AF: 0.185 AC: 892 AN: 4810

European-Finnish (FIN) AF: 0.0221 AC: 234 AN: 10592

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.0479 AC: 3259 AN: 68006

Other (OTH) AF: 0.0852 AC: 180 AN: 2112

Alfa AF: 0.0594 Hom.: 1429

Bravo AF: 0.0615

TwinsUK AF: 0.0453 AC: 168

ALSPAC AF: 0.0493 AC: 190

ESP6500AA AF: 0.0431 AC: 190

ESP6500EA AF: 0.0509 AC: 438

ExAC AF: 0.0809 AC: 9816

Asia WGS AF: 0.199 AC: 691 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.9
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.21
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.010	D
Vest4		0.24
MPC		0.53
ClinPred		0.022	T
GERP RS		4.5
gMVP		0.59
Mutation Taster		=91/9	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: rs1868463; hg19: chr13-39266484; COSMIC: COSV54837971;