13-38766281-T-G

Variant names:

• chr13-38766281-T-G
• rs12865228
• NM_207361.6:c.5410+1831T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_207361.6(FREM2):​c.5410+1831T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,178 control chromosomes in the GnomAD database, including 2,145 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (2145 hom., cov: 32)
• Consequence: FREM2 NM_207361.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM2	NM_207361.6	c.5410+1831T>G		intron_variant	Intron 3 of 23	ENST00000280481.9	NP_997244.4
FREM2	XR_941571.3	n.5678+1831T>G		intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM2	ENST00000280481.9	c.5410+1831T>G		intron_variant	Intron 3 of 23	1	NM_207361.6	ENSP00000280481.7

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24045 AN: 152058 Hom.: 2145 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.149

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.158 AC: 24050 AN: 152178 Hom.: 2145 Cov.: 32 AF XY: 0.158 AC XY: 11766 AN XY: 74400

African (AFR) AF: 0.115 AC: 4778 AN: 41542

American (AMR) AF: 0.160 AC: 2451 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 575 AN: 3468

East Asian (EAS) AF: 0.406 AC: 2098 AN: 5166

South Asian (SAS) AF: 0.178 AC: 855 AN: 4804

European-Finnish (FIN) AF: 0.104 AC: 1101 AN: 10610

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11623 AN: 67996

Other (OTH) AF: 0.150 AC: 316 AN: 2110

Alfa AF: 0.167 Hom.: 6542

Bravo AF: 0.161

Asia WGS AF: 0.252 AC: 877 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.9
DANN	Benign	0.71
PhyloP100		1.8
Mutation Taster		=100/0	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: rs12865228; hg19: chr13-39340418;