13-38769670-G-T

Position:

• chr13-38769670-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_207361.6(FREM2):​c.5503G>T​(p.Ala1835Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: FREM2 NM_207361.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FREM2	NM_207361.6	c.5503G>T	p.Ala1835Ser	missense_variant	4/24	ENST00000280481.9	NP_997244.4
FREM2	XR_941571.3	n.5771G>T		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FREM2	ENST00000280481.9	c.5503G>T	p.Ala1835Ser	missense_variant	4/24	1	NM_207361.6	ENSP00000280481.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251216 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.75	T
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.28
Sift	Benign	0.036	D
Sift4G	Uncertain	0.019	D
Vest4		0.72
MutPred		0.49		Gain of disorder (P = 0.0298);
MVP		0.65
MPC		0.26
ClinPred		0.89	D
GERP RS		5.0
gMVP		0.48

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: rs767743882; hg19: chr13-39343807;