22-23837757-T-G

Variant names:

• chr22-23837757-T-G
• NM_001002862.3:c.425A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001002862.3(DERL3):​c.425A>C​(p.Asn142Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DERL3 NM_001002862.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.96

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DERL3	NM_001002862.3	c.425A>C	p.Asn142Thr	missense_variant	Exon 5 of 7	ENST00000318109.12	NP_001002862.1
SMARCB1	NM_003073.5	c.*3577T>G		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.425A>C	p.Asn142Thr	missense_variant	Exon 5 of 7	1	NM_001002862.3	ENSP00000315303.8
SMARCB1	ENST00000644036.2	c.*3577T>G		3_prime_UTR_variant	Exon 9 of 9		NM_003073.5	ENSP00000494049.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461730 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;T;.
Eigen	Benign	0.047
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Benign	0.19
Sift	Benign	0.082	T;T;T
Sift4G	Benign	0.086	T;T;T
Polyphen		0.36	B;B;.
Vest4		0.78
MutPred		0.85		Loss of MoRF binding (P = 0.1086);Loss of MoRF binding (P = 0.1086);Loss of MoRF binding (P = 0.1086);
MVP		0.70
MPC		0.18
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.51
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-24179944;