22-41620695-C-G

Variant names:

• chr22-41620695-C-G
• rs2267437
• NM_015704.3:c.88+57G>C

Variant summary

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

The NM_015704.3(DESI1):​c.88+57G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 1,529,408 control chromosomes in the GnomAD database, including 133,277 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 0.34 (9761 hom., cov: 32)
  • Exomes 𝑓: 0.42 (123516 hom.)
• Consequence: DESI1 NM_015704.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168
• Publications: 77 publications found

Genes affected

DESI1 (HGNC:24577): (desumoylating isopeptidase 1) Enables importin-alpha family protein binding activity. Involved in protein export from nucleus and regulation of proteasomal ubiquitin-dependent protein catabolic process. Located in cytosol. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

XRCC6 (HGNC:4055): (X-ray repair cross complementing 6) The p70/p80 autoantigen is a nuclear complex consisting of two subunits with molecular masses of approximately 70 and 80 kDa. The complex functions as a single-stranded DNA-dependent ATP-dependent helicase. The complex may be involved in the repair of nonhomologous DNA ends such as that required for double-strand break repair, transposition, and V(D)J recombination. High levels of autoantibodies to p70 and p80 have been found in some patients with systemic lupus erythematosus. [provided by RefSeq, Jul 2008]

XRCC6 Gene-Disease associations (from GenCC):

• autism spectrum 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 (BayesDel_noAF=-0.65).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015704.3. 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
	DESI1	NM_015704.3	MANE Select	c.88+57G>C		intron	N/A	NP_056519.1	Q6ICB0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DESI1	ENST00000263256.7	TSL:1 MANE Select	c.88+57G>C		intron	N/A	ENSP00000263256.6	Q6ICB0
	DESI1	ENST00000938248.1		c.88+57G>C		intron	N/A	ENSP00000608307.1
	DESI1	ENST00000881058.1		c.88+57G>C		intron	N/A	ENSP00000551117.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51197 AN: 151994 Hom.: 9762 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.328

GnomAD4 exome AF: 0.417 AC: 574251 AN: 1377296 Hom.: 123516 AF XY: 0.418 AC XY: 284963 AN XY: 681606

African (AFR) AF: 0.168 AC: 5171 AN: 30830

American (AMR) AF: 0.195 AC: 6682 AN: 34204

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 9755 AN: 24270

East Asian (EAS) AF: 0.280 AC: 10103 AN: 36020

South Asian (SAS) AF: 0.380 AC: 30200 AN: 79386

European-Finnish (FIN) AF: 0.410 AC: 20268 AN: 49458

Middle Eastern (MID) AF: 0.357 AC: 1958 AN: 5484

European-Non Finnish (NFE) AF: 0.442 AC: 468493 AN: 1060588

Other (OTH) AF: 0.379 AC: 21621 AN: 57056

GnomAD4 genome AF: 0.337 AC: 51186 AN: 152112 Hom.: 9761 Cov.: 32 AF XY: 0.332 AC XY: 24714 AN XY: 74344

African (AFR) AF: 0.181 AC: 7510 AN: 41538

American (AMR) AF: 0.268 AC: 4098 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1426 AN: 3466

East Asian (EAS) AF: 0.203 AC: 1045 AN: 5158

South Asian (SAS) AF: 0.371 AC: 1789 AN: 4816

European-Finnish (FIN) AF: 0.399 AC: 4217 AN: 10576

Middle Eastern (MID) AF: 0.401 AC: 117 AN: 292

European-Non Finnish (NFE) AF: 0.441 AC: 29951 AN: 67960

Other (OTH) AF: 0.325 AC: 685 AN: 2110

Alfa AF: 0.264 Hom.: 778

Bravo AF: 0.314

Asia WGS AF: 0.266 AC: 927 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Benign	0.91
PhyloP100		-0.17
PromoterAI		-0.047	Neutral
RBP_binding_hub_radar		0.91
RBP_regulation_power_radar		3.4
Mutation Taster		=15/85	disease causing

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: rs2267437; hg19: chr22-42016699; COSMIC: COSV54354615; COSMIC: COSV54354615;