11-73969996-T-G

Variant names:

• chr11-73969996-T-G
• rs754776389
• NM_153614.4:c.833T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_153614.4(DNAJB13):​c.833T>G​(p.Met278Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M278T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAJB13 NM_153614.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.03
• Publications: 3 publications found

Genes affected

DNAJB13 (HGNC:30718): (DnaJ heat shock protein family (Hsp40) member B13) This gene encodes a member of the heat shock protein 40 co-chaperone family which is produced in large amounts in the testis and is located on the radial spokes of the axoneme in human sperm flagella and other flagellar structures. The encoded protein associates with the sperm annulus, as part of the septin complex, through direct interaction with septin 4, during sperm terminal differentiation. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and male infertility. [provided by RefSeq, Apr 2017]

DNAJB13 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 34

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 11-73969996-T-G is Pathogenic according to our data. Variant chr11-73969996-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 253328.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB13	NM_153614.4	c.833T>G	p.Met278Arg	missense_variant	Exon 8 of 8	ENST00000339764.6	NP_705842.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJB13	ENST00000339764.6	c.833T>G	p.Met278Arg	missense_variant	Exon 8 of 8	1	NM_153614.4	ENSP00000344431.1
DNAJB13	ENST00000543947.1	c.308T>G	p.Met103Arg	missense_variant	Exon 5 of 6	1		ENSP00000438576.1
DNAJB13	ENST00000542350.5	c.533T>G	p.Met178Arg	missense_variant	Exon 5 of 5	3		ENSP00000440778.1
DNAJB13	ENST00000537753.5	c.308T>G	p.Met103Arg	missense_variant	Exon 5 of 5	3		ENSP00000439711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Primary ciliary dyskinesia 34 Pathogenic:1

Aug 31, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.043	D
MutationAssessor	Pathogenic	4.5	H;.;.
PhyloP100		7.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.93
MutPred		0.84		Gain of methylation at M278 (P = 0.0174);.;.;
MVP		0.70
MPC		1.1
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.93
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754776389; hg19: chr11-73681041;