rs17017968

Positions:

• chr4-143621060-A-G
• chr4-143621060-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001168235.2(FREM3):​c.5756T>C​(p.Ile1919Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,537,210 control chromosomes in the GnomAD database, including 3,426 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.090 (1759 hom., cov: 32)
  • Exomes 𝑓: 0.014 (1667 hom.)
• Consequence: FREM3 NM_001168235.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64

Genes affected

FREM3 (HGNC:25172): (FRAS1 related extracellular matrix 3) This gene encodes an integral membrane protein containing numerous CSPG (chondroitin sulfate proteoglycan element) repeats and Calx-beta domains. The protein belongs to the family of FRAS1/FREM extracellular matrix proteins and may play a role cell adhesion. [provided by RefSeq, Feb 2017]

GUSBP5 (HGNC:42319): (GUSB pseudogene 5)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010958254).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM3	NM_001168235.2	c.5756T>C	p.Ile1919Thr	missense_variant	5/8	ENST00000329798.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM3	ENST00000329798.5	c.5756T>C	p.Ile1919Thr	missense_variant	5/8	5	NM_001168235.2	P1
GUSBP5	ENST00000641328.1	n.861+48479A>G		intron_variant, non_coding_transcript_variant
GUSBP5	ENST00000511042.5	n.192-24025A>G		intron_variant, non_coding_transcript_variant		5
FREM3	ENST00000508899.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0892 AC: 13566 AN: 152058 Hom.: 1744 Cov.: 32

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0606

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00460

Gnomad OTH AF: 0.0689

GnomAD3 exomes AF: 0.0285 AC: 4084 AN: 143092 Hom.: 389 AF XY: 0.0236 AC XY: 1798 AN XY: 76340

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.0560

Gnomad SAS exome AF: 0.00590

Gnomad FIN exome AF: 0.000429

Gnomad NFE exome AF: 0.00535

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0138 AC: 19113 AN: 1385034 Hom.: 1667 Cov.: 30 AF XY: 0.0128 AC XY: 8776 AN XY: 683432

Gnomad4 AFR exome AF: 0.307

Gnomad4 AMR exome AF: 0.0225

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.0382

Gnomad4 SAS exome AF: 0.00687

Gnomad4 FIN exome AF: 0.000684

Gnomad4 NFE exome AF: 0.00391

Gnomad4 OTH exome AF: 0.0321

GnomAD4 genome AF: 0.0896 AC: 13631 AN: 152176 Hom.: 1759 Cov.: 32 AF XY: 0.0878 AC XY: 6534 AN XY: 74412

Gnomad4 AFR AF: 0.293

Gnomad4 AMR AF: 0.0396

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.0602

Gnomad4 SAS AF: 0.00932

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00460

Gnomad4 OTH AF: 0.0682

Alfa AF: 0.0165 Hom.: 414

Bravo AF: 0.102

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.278 AC: 385

ESP6500EA AF: 0.00503 AC: 16

ExAC AF: 0.0340 AC: 805

Asia WGS AF: 0.0640 AC: 222 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.9
DANN	Benign	0.71
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.92	N
MutationTaster	Benign	0.97	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.13
Sift	Benign	0.57	T
Sift4G	Benign	0.46	T
Vest4		0.017
ClinPred		0.0041	T
GERP RS		-4.4
Varity_R		0.045
gMVP		0.49

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: rs17017968; hg19: chr4-144542213;