4-143585880-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001168235.2(FREM3):c.6142G>A(p.Val2048Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,537,254 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (32 hom.)
• Consequence: FREM3 NM_001168235.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.47

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003987968).
• BP6: Variant 4-143585880-C-T is Benign according to our data. Variant chr4-143585880-C-T is described in ClinVar as [Benign]. Clinvar id is 780493.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1960/152256) while in subpopulation AFR AF= 0.0447 (1857/41526). AF 95% confidence interval is 0.043. There are 41 homozygotes in gnomad4. There are 922 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FREM3	NM_001168235.2	c.6142G>A	p.Val2048Met	missense_variant	7/8	ENST00000329798.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FREM3	ENST00000329798.5	c.6142G>A	p.Val2048Met	missense_variant	7/8	5	NM_001168235.2	P1
GUSBP5	ENST00000641328.1	n.861+13299C>T		intron_variant, non_coding_transcript_variant
GUSBP5	ENST00000511042.5	n.191+13299C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1955 AN: 152138 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0447

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00299 AC: 431 AN: 144232 Hom.: 7 AF XY: 0.00225 AC XY: 173 AN XY: 76934

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.00207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000121

Gnomad OTH exome AF: 0.00138

GnomAD4 exome AF: 0.00130 AC: 1794 AN: 1384998 Hom.: 32 Cov.: 31 AF XY: 0.00110 AC XY: 755 AN XY: 683424

Gnomad4 AFR exome AF: 0.0457

Gnomad4 AMR exome AF: 0.00263

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000353

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000501

Gnomad4 OTH exome AF: 0.00281

GnomAD4 genome AF: 0.0129 AC: 1960 AN: 152256 Hom.: 41 Cov.: 32 AF XY: 0.0124 AC XY: 922 AN XY: 74458

Gnomad4 AFR AF: 0.0447

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00150 Hom.: 7

Bravo AF: 0.0143

ESP6500AA AF: 0.0419 AC: 58

ESP6500EA AF: 0.000629 AC: 2

ExAC AF: 0.00483 AC: 127

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Vest4		0.30
MVP		0.30
ClinPred		0.083	T
GERP RS		0.46
Varity_R		0.11
gMVP		0.66

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: rs78440529; hg19: chr4-144507033;