3-38138675-G-T

Variant names:

• chr3-38138675-G-T
• rs1700983375
• NM_002468.5:c.-26G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002468.5(MYD88):​c.-26G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,567,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MYD88 NM_002468.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.231
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ENSG00000299092 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06931457).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002468.5. 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
	MYD88	NM_002468.5	MANE Select	c.-26G>T		5_prime_UTR	Exon 1 of 5	NP_002459.3	Q99836-1
	MYD88	NM_001172567.2		c.-26G>T		5_prime_UTR	Exon 1 of 5	NP_001166038.2	Q99836-6
	MYD88	NM_001172568.2		c.-26G>T		5_prime_UTR	Exon 1 of 4	NP_001166039.2	Q99836-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYD88	ENST00000650905.2	MANE Select	c.-26G>T		5_prime_UTR	Exon 1 of 5	ENSP00000498360.2	Q99836-1
	MYD88	ENST00000421516.3	TSL:1	c.-26G>T		5_prime_UTR	Exon 1 of 5	ENSP00000391753.3	Q99836-6
	MYD88	ENST00000417037.8	TSL:1	c.-26G>T		5_prime_UTR	Exon 1 of 4	ENSP00000401399.4	Q99836-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1415066 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 698404

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32380

American (AMR) AF: 0.00 AC: 0 AN: 41246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24108

East Asian (EAS) AF: 0.00 AC: 0 AN: 38918

South Asian (SAS) AF: 0.00 AC: 0 AN: 82314

European-Finnish (FIN) AF: 0.0000211 AC: 1 AN: 47474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085148

Other (OTH) AF: 0.00 AC: 0 AN: 58190

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Pyogenic bacterial infections due to MyD88 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.2
DANN	Benign	0.87
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.23
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.028
Sift	Benign	0.071	T
Sift4G	Benign	0.29	T
Vest4		0.13
MutPred		0.16		Loss of methylation at P5 (P = 0.0294)
MVP		0.14
MPC		1.0
ClinPred		0.32	T
GERP RS		0.088
PromoterAI		-0.059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1700983375; hg19: chr3-38180166;