chr4-143611491-A-G

Variant names:

• chr4-143611491-A-G
• rs72938299
• NM_001168235.2:c.5816T>C

Variant summary

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

The NM_001168235.2(FREM3):​c.5816T>C​(p.Phe1939Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,537,030 control chromosomes in the GnomAD database, including 957 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.048 (465 hom., cov: 33)
  • Exomes 𝑓: 0.0094 (492 hom.)
• Consequence: FREM3 NM_001168235.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.30
• Publications: 7 publications found

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:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016269386).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001168235.2. 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
	FREM3	NM_001168235.2	MANE Select	c.5816T>C	p.Phe1939Ser	missense	Exon 6 of 8	NP_001161707.1	P0C091

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM3	ENST00000329798.5	TSL:5 MANE Select	c.5816T>C	p.Phe1939Ser	missense	Exon 6 of 8	ENSP00000332886.5	P0C091
	FREM3	ENST00000508899.1	TSL:5	n.53T>C		non_coding_transcript_exon	Exon 2 of 3
	GUSBP5	ENST00000511042.5	TSL:5	n.192-33594A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0477 AC: 7258 AN: 152170 Hom.: 465 Cov.: 33

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0591

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0190 AC: 2699 AN: 141946 AF XY: 0.0163

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.0142

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.0539

Gnomad FIN exome AF: 0.000432

Gnomad NFE exome AF: 0.00503

Gnomad OTH exome AF: 0.0172

GnomAD4 exome AF: 0.00938 AC: 12984 AN: 1384742 Hom.: 492 Cov.: 31 AF XY: 0.00895 AC XY: 6114 AN XY: 683304

African (AFR) AF: 0.152 AC: 4811 AN: 31562

American (AMR) AF: 0.0154 AC: 548 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 354 AN: 25174

East Asian (EAS) AF: 0.0372 AC: 1330 AN: 35732

South Asian (SAS) AF: 0.00627 AC: 497 AN: 79226

European-Finnish (FIN) AF: 0.000686 AC: 24 AN: 35002

Middle Eastern (MID) AF: 0.0376 AC: 214 AN: 5696

European-Non Finnish (NFE) AF: 0.00370 AC: 3995 AN: 1078740

Other (OTH) AF: 0.0209 AC: 1211 AN: 57910

GnomAD4 genome AF: 0.0477 AC: 7270 AN: 152288 Hom.: 465 Cov.: 33 AF XY: 0.0466 AC XY: 3470 AN XY: 74482

African (AFR) AF: 0.147 AC: 6111 AN: 41530

American (AMR) AF: 0.0241 AC: 368 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.0587 AC: 304 AN: 5180

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4832

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10630

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00426 AC: 290 AN: 68028

Other (OTH) AF: 0.0407 AC: 86 AN: 2114

Alfa AF: 0.0234 Hom.: 416

Bravo AF: 0.0550

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.149 AC: 206

ESP6500EA AF: 0.00503 AC: 16

ExAC AF: 0.0187 AC: 439

Asia WGS AF: 0.0510 AC: 177 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.065
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0040	D
Vest4		0.045
ClinPred		0.039	T
GERP RS		1.4
Varity_R		0.13
gMVP		0.91
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs72938299; hg19: chr4-144532644;