rs201871349

chr3-38138780-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002468.5(MYD88):c.80T>C(p.Met27Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000596 in 1,613,156 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (21 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (7 hom.)
• Consequence: MYD88 NM_002468.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 3.19

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007021904).
• BP6: Variant 3-38138780-T-C is Benign according to our data. Variant chr3-38138780-T-C is described in ClinVar as [Benign]. Clinvar id is 134871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00345 (526/152286) while in subpopulation AMR AF= 0.0343 (524/15294). AF 95% confidence interval is 0.0318. There are 21 homozygotes in gnomad4. There are 362 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYD88	NM_002468.5	c.80T>C	p.Met27Thr	missense_variant	1/5	ENST00000650905.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYD88	ENST00000650905.2	c.80T>C	p.Met27Thr	missense_variant	1/5		NM_002468.5	A1

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152168 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0343

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: 0.000956

GnomAD3 exomes AF: 0.00125 AC: 313 AN: 249818 Hom.: 8 AF XY: 0.00104 AC XY: 141 AN XY: 135584

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.00885

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: 0.00

Gnomad OTH exome AF: 0.000984

GnomAD4 exome AF: 0.000298 AC: 435 AN: 1460870 Hom.: 7 Cov.: 31 AF XY: 0.000248 AC XY: 180 AN XY: 726770

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.00345 AC: 526 AN: 152286 Hom.: 21 Cov.: 33 AF XY: 0.00486 AC XY: 362 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0343

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.00304

ExAC AF: 0.000264 AC: 32

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyogenic bacterial infections due to MyD88 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

MYD88-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	22
Dann	Benign	0.95
DEOGEN2	Benign	0.021	T;.;T;.;.;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;D;T;D;D;D;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0070	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.3	N;.;.;.;.;N;.;.
REVEL	Benign	0.079
Sift	Benign	0.33	T;.;.;.;.;T;.;.
Sift4G	Uncertain	0.056	T;.;.;.;.;T;.;.
Polyphen		0.087, 0.032	.;.;B;B;.;.;.;.
Vest4		0.21
MVP		0.49
MPC		0.65
ClinPred		0.049	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs201871349; hg19: chr3-38180271; COSMIC: COSV57182191; COSMIC: COSV57182191;