chr3-38138670-CGACCGCGCTGAGGCTCCAG-C

Variant names:

• chr3-38138670-CGACCGCGCTGAGGCTCCAG-C
• rs746651350
• ENST00000416282.3:n.27_45delGCTGAGGCTCCAGGACCGC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The ENST00000416282.3(MYD88):​n.27_45delGCTGAGGCTCCAGGACCGC variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00055 in 1,561,362 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: MYD88 ENST00000416282.3 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 O:1
• Conservation: PhyloP100: 0.231
• Publications: 2 publications found

Genes affected

MYD88 (HGNC:7562): (MYD88 innate immune signal transduction adaptor) This gene encodes a cytosolic adapter protein that plays a central role in the innate and adaptive immune response. This protein functions as an essential signal transducer in the interleukin-1 and Toll-like receptor signaling pathways. These pathways regulate that activation of numerous proinflammatory genes. The encoded protein consists of an N-terminal death domain and a C-terminal Toll-interleukin1 receptor domain. Patients with defects in this gene have an increased susceptibility to pyogenic bacterial infections. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

MYD88 Gene-Disease associations (from GenCC):

• pyogenic bacterial infections due to MyD88 deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000299092 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP5: Variant 3-38138670-CGACCGCGCTGAGGCTCCAG-C is Pathogenic according to our data. Variant chr3-38138670-CGACCGCGCTGAGGCTCCAG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469578.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYD88	NM_002468.5	c.-24_-6delGCTGAGGCTCCAGGACCGC		5_prime_UTR_variant	Exon 1 of 5	ENST00000650905.2	NP_002459.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYD88	ENST00000650905.2	c.-24_-6delGCTGAGGCTCCAGGACCGC		5_prime_UTR_variant	Exon 1 of 5		NM_002468.5	ENSP00000498360.2

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000364 AC: 75 AN: 206006 AF XY: 0.000360

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000640

Gnomad OTH exome AF: 0.000603

GnomAD4 exome AF: 0.000578 AC: 814 AN: 1409132 Hom.: 0 AF XY: 0.000540 AC XY: 375 AN XY: 694786

African (AFR) AF: 0.0000621 AC: 2 AN: 32224

American (AMR) AF: 0.000346 AC: 14 AN: 40434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23466

East Asian (EAS) AF: 0.00 AC: 0 AN: 38774

South Asian (SAS) AF: 0.00 AC: 0 AN: 80632

European-Finnish (FIN) AF: 0.0000429 AC: 2 AN: 46598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5204

European-Non Finnish (NFE) AF: 0.000711 AC: 771 AN: 1083860

Other (OTH) AF: 0.000431 AC: 25 AN: 57940

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74374

African (AFR) AF: 0.000121 AC: 5 AN: 41458

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68042

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000288 Hom.: 0

Bravo AF: 0.000351

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pyogenic bacterial infections due to MyD88 deficiency Pathogenic:1 Uncertain:1 Other:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala6Profs*39) in the MYD88 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYD88 are known to be pathogenic (PMID: 18669862, 20538326). This variant is present in population databases (rs746651350, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with MYD88-related conditions. ClinVar contains an entry for this variant (Variation ID: 469578). For these reasons, this variant has been classified as Pathogenic. -

May 29, 2020

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Uncertain significance and reported on 09-01-2023 by Children's Hospital of Philadelphia. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

MYD88-related disorder Uncertain:1

Feb 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYD88 c.16_34del19 variant is predicted to result in a frameshift and premature protein termination (p.Ala6Profs*39). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be causative of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746651350; hg19: chr3-38180161; COSMIC: COSV104622180;