rs746651350

chr3-38138670-CGACCGCGCTGAGGCTCCAG-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BS1_Supporting

The NM_002468.5(MYD88):c.-24_-6del variant causes a 5 prime UTR 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. 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 NM_002468.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 0.231

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 469578.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000578 (814/1409132) while in subpopulation NFE AF= 0.000711 (771/1083860). AF 95% confidence interval is 0.00067. There are 0 homozygotes in gnomad4_exome. There are 375 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYD88	NM_002468.5	c.-24_-6del		5_prime_UTR_variant	1/5	ENST00000650905.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYD88	ENST00000650905.2	c.-24_-6del		5_prime_UTR_variant	1/5		NM_002468.5	A1

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

GnomAD3 exomes AF: 0.000364 AC: 75 AN: 206006 Hom.: 0 AF XY: 0.000360 AC XY: 41 AN XY: 113806

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 SAS 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

Gnomad4 AFR exome AF: 0.0000621

Gnomad4 AMR exome AF: 0.000346

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000429

Gnomad4 NFE exome AF: 0.000711

Gnomad4 OTH exome AF: 0.000431

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

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000288 Hom.: 0

Bravo AF: 0.000351

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	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. -

MYD88-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2024

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs746651350; hg19: chr3-38180161;