rs3177243

Variant names:

• chr22-23837735-G-C
• rs3177243
• NM_001002862.3:c.447C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-23837735-G-C
• chr22-23837735-G-T

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 25 publications found

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]

SMARCB1 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• intellectual disability, autosomal dominant 15

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• rhabdoid tumor predisposition syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• SMARCB1-related schwannomatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
• familial multiple meningioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• schwannomatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
DERL3	NM_001002862.3	c.447C>G	p.Phe149Leu	missense_variant	Exon 5 of 7	ENST00000318109.12	NP_001002862.1
SMARCB1	NM_003073.5	c.*3555G>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000644036.2	NP_003064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DERL3	ENST00000318109.12	c.447C>G	p.Phe149Leu	missense_variant	Exon 5 of 7	1	NM_001002862.3	ENSP00000315303.8
SMARCB1	ENST00000644036.2	c.*3555G>C		3_prime_UTR_variant	Exon 9 of 9		NM_003073.5	ENSP00000494049.2

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

GnomAD2 exomes AF: 0.129 AC: 32213 AN: 250536 AF XY: 0.125

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 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

African (AFR) AF: 0.265 AC: 8873 AN: 33462

American (AMR) AF: 0.0825 AC: 3689 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3719 AN: 26130

East Asian (EAS) AF: 0.0259 AC: 1029 AN: 39700

South Asian (SAS) AF: 0.0442 AC: 3809 AN: 86246

European-Finnish (FIN) AF: 0.154 AC: 8195 AN: 53268

Middle Eastern (MID) AF: 0.180 AC: 1035 AN: 5756

European-Non Finnish (NFE) AF: 0.153 AC: 169898 AN: 1111786

Other (OTH) AF: 0.146 AC: 8786 AN: 60374

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

African (AFR) AF: 0.257 AC: 10676 AN: 41496

American (AMR) AF: 0.128 AC: 1959 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 482 AN: 3470

East Asian (EAS) AF: 0.0170 AC: 88 AN: 5184

South Asian (SAS) AF: 0.0378 AC: 182 AN: 4820

European-Finnish (FIN) AF: 0.160 AC: 1693 AN: 10610

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.156 AC: 10620 AN: 67974

Other (OTH) AF: 0.153 AC: 322 AN: 2110

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
PhyloP100		4.0
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
Mutation Taster		=41/59	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3177243; hg19: chr22-24179922; COSMIC: COSV51956239; COSMIC: COSV51956239;