rs3177243

Positions:

• chr22-23837735-G-C

Variant summary

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

The NM_001002862.3(DERL3):​c.447C>G​(p.Phe149Leu) variant causes a missense change. The variant allele was found at a frequency of 0.146 in 1,613,610 control chromosomes in the GnomAD database, including 18,754 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.17 (2451 hom., cov: 33)
  • Exomes 𝑓: 0.14 (16303 hom.)
• Consequence: DERL3 NM_001002862.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.00

Genes affected

DERL3 (HGNC:14236): (derlin 3) The protein encoded by this gene belongs to the derlin family, and resides in the endoplasmic reticulum (ER). Proteins that are unfolded or misfolded in the ER must be refolded or degraded to maintain the homeostasis of the ER. This protein appears to be involved in the degradation of misfolded glycoproteins in the ER. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Oct 2008]

SMARCB1 (HGNC:11103): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017095208).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DERL3	NM_001002862.3	c.447C>G	p.Phe149Leu	missense_variant	5/7	ENST00000318109.12
SMARCB1	NM_003073.5	c.*3555G>C		3_prime_UTR_variant	9/9	ENST00000644036.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DERL3	ENST00000318109.12	c.447C>G	p.Phe149Leu	missense_variant	5/7	1	NM_001002862.3	P1
SMARCB1	ENST00000644036.2	c.*3555G>C		3_prime_UTR_variant	9/9		NM_003073.5	A1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26170 AN: 152060 Hom.: 2452 Cov.: 33

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.0169

Gnomad SAS AF: 0.0373

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.154

GnomAD3 exomes AF: 0.129 AC: 32213 AN: 250536 Hom.: 2507 AF XY: 0.125 AC XY: 16949 AN XY: 135636

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.0783

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0141

Gnomad SAS exome AF: 0.0425

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.143 AC: 209033 AN: 1461432 Hom.: 16303 Cov.: 35 AF XY: 0.140 AC XY: 101942 AN XY: 727002

Gnomad4 AFR exome AF: 0.265

Gnomad4 AMR exome AF: 0.0825

Gnomad4 ASJ exome AF: 0.142

Gnomad4 EAS exome AF: 0.0259

Gnomad4 SAS exome AF: 0.0442

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.172 AC: 26188 AN: 152178 Hom.: 2451 Cov.: 33 AF XY: 0.168 AC XY: 12531 AN XY: 74394

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.0378

Gnomad4 FIN AF: 0.160

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.153

Alfa AF: 0.155 Hom.: 1375

Bravo AF: 0.176

TwinsUK AF: 0.140 AC: 518

ALSPAC AF: 0.144 AC: 555

ESP6500AA AF: 0.255 AC: 1124

ESP6500EA AF: 0.159 AC: 1367

ExAC AF: 0.134 AC: 16295

Asia WGS AF: 0.0470 AC: 164 AN: 3478

EpiCase AF: 0.163

EpiControl AF: 0.159

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;M;M
MutationTaster	Benign	1.1e-9	P;P;P;P
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Benign	0.12
Sift	Benign	0.049	D;D;D
Sift4G	Benign	0.20	T;T;T
Polyphen		0.058	B;B;.
Vest4		0.17
MutPred		0.32		Loss of MoRF binding (P = 0.2609);Loss of MoRF binding (P = 0.2609);Loss of MoRF binding (P = 0.2609);
MPC		0.18
ClinPred		0.029	T
GERP RS		5.3
Varity_R		0.65
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3177243; hg19: chr22-24179922; COSMIC: COSV51956239; COSMIC: COSV51956239;