chr22-23836945-G-A

Variant names:

• chr22-23836945-G-A
• rs1128127
• NM_001002862.3:c.632C>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.632C>T​(p.Ala211Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,584,594 control chromosomes in the GnomAD database, including 23,167 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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 0.23 (5575 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17592 hom.)
• Consequence: DERL3 NM_001002862.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.95
• Publications: 47 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=4.0331483E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002862.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DERL3	NM_001002862.3	MANE Select	c.632C>T	p.Ala211Val	missense	Exon 7 of 7	NP_001002862.1
	SMARCB1	NM_003073.5	MANE Select	c.*2765G>A		3_prime_UTR	Exon 9 of 9	NP_003064.2
	SMARCB1	NM_001362877.2		c.*2765G>A		3_prime_UTR	Exon 9 of 9	NP_001349806.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DERL3	ENST00000318109.12	TSL:1 MANE Select	c.632C>T	p.Ala211Val	missense	Exon 7 of 7	ENSP00000315303.8
	SMARCB1	ENST00000644036.2	MANE Select	c.*2765G>A		3_prime_UTR	Exon 9 of 9	ENSP00000494049.2
	DERL3	ENST00000476077.1	TSL:1	c.*115C>T		3_prime_UTR	Exon 6 of 6	ENSP00000419399.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34194 AN: 151598 Hom.: 5559 Cov.: 32

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.214

GnomAD2 exomes AF: 0.166 AC: 35198 AN: 211492 AF XY: 0.166

Gnomad AFR exome AF: 0.475

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.141 AC: 202528 AN: 1432878 Hom.: 17592 Cov.: 38 AF XY: 0.144 AC XY: 102353 AN XY: 710772

African (AFR) AF: 0.475 AC: 15443 AN: 32544

American (AMR) AF: 0.119 AC: 4707 AN: 39446

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 3903 AN: 24624

East Asian (EAS) AF: 0.0674 AC: 2621 AN: 38896

South Asian (SAS) AF: 0.271 AC: 22268 AN: 82032

European-Finnish (FIN) AF: 0.132 AC: 6877 AN: 52190

Middle Eastern (MID) AF: 0.214 AC: 1202 AN: 5628

European-Non Finnish (NFE) AF: 0.124 AC: 135708 AN: 1098426

Other (OTH) AF: 0.166 AC: 9799 AN: 59092

GnomAD4 genome AF: 0.226 AC: 34240 AN: 151716 Hom.: 5575 Cov.: 32 AF XY: 0.224 AC XY: 16589 AN XY: 74144

African (AFR) AF: 0.460 AC: 18985 AN: 41312

American (AMR) AF: 0.149 AC: 2277 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 522 AN: 3462

East Asian (EAS) AF: 0.101 AC: 516 AN: 5132

South Asian (SAS) AF: 0.277 AC: 1329 AN: 4806

European-Finnish (FIN) AF: 0.132 AC: 1389 AN: 10544

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8545 AN: 67888

Other (OTH) AF: 0.212 AC: 447 AN: 2108

Alfa AF: 0.163 Hom.: 8102

Bravo AF: 0.233

TwinsUK AF: 0.122 AC: 454

ALSPAC AF: 0.112 AC: 430

ESP6500AA AF: 0.456 AC: 2009

ESP6500EA AF: 0.126 AC: 1080

ExAC AF: 0.165 AC: 19961

Asia WGS AF: 0.200 AC: 698 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.76	D
MetaRNN	Benign	0.00040	T
MetaSVM	Benign	-0.92	T
PhyloP100		2.9
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.084
Sift	Benign	0.27	T
Sift4G	Benign	0.26	T
Polyphen		0.0070	B
Vest4		0.014
ClinPred		0.010	T
GERP RS		2.3
Varity_R		0.043
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1128127; hg19: chr22-24179132; COSMIC: COSV51956055; COSMIC: COSV51956055;