rs768025686

Variant names:

• chr3-38138731-G-A
• rs768025686
• NM_002468.5:c.31G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002468.5(MYD88):​c.31G>A​(p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000996 in 1,606,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MYD88 NM_002468.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.065250576).

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.31G>A	p.Ala11Thr	missense	Exon 1 of 5	NP_002459.3	Q99836-1
	MYD88	NM_001172567.2		c.31G>A	p.Ala11Thr	missense	Exon 1 of 5	NP_001166038.2	Q99836-6
	MYD88	NM_001172568.2		c.31G>A	p.Ala11Thr	missense	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.31G>A	p.Ala11Thr	missense	Exon 1 of 5	ENSP00000498360.2	Q99836-1
	MYD88	ENST00000421516.3	TSL:1	c.31G>A	p.Ala11Thr	missense	Exon 1 of 5	ENSP00000391753.3	Q99836-6
	MYD88	ENST00000417037.8	TSL:1	c.31G>A	p.Ala11Thr	missense	Exon 1 of 4	ENSP00000401399.4	Q99836-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000123 AC: 3 AN: 243956 AF XY: 0.00000749

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.00000962 AC: 14 AN: 1454688 Hom.: 0 Cov.: 31 AF XY: 0.0000125 AC XY: 9 AN XY: 722568

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51324

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5738

European-Non Finnish (NFE) AF: 0.00000993 AC: 11 AN: 1107702

Other (OTH) AF: 0.0000166 AC: 1 AN: 60126

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	0.074
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.053
Sift	Benign	0.085	T
Sift4G	Benign	0.50	T
Polyphen		0.0030	B
Vest4		0.11
MutPred		0.12		Loss of glycosylation at P6 (P = 0.0388)
MVP		0.49
MPC		1.1
ClinPred		0.12	T
GERP RS		2.1
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.017
Mutation Taster		=86/14	polymorphism

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: rs768025686; hg19: chr3-38180222; COSMIC: COSV57181906; COSMIC: COSV57181906;