11-73958330-G-T

Variant names:

• chr11-73958330-G-T
• rs1950819983
• NM_153614.4:c.82G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_153614.4(DNAJB13):​c.82G>T​(p.Ala28Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAJB13 NM_153614.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.79
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB13	NM_153614.4	c.82G>T	p.Ala28Ser	missense_variant	Exon 2 of 8	ENST00000339764.6	NP_705842.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJB13	ENST00000339764.6	c.82G>T	p.Ala28Ser	missense_variant	Exon 2 of 8	1	NM_153614.4	ENSP00000344431.1
DNAJB13	ENST00000535730.1	n.126G>T		non_coding_transcript_exon_variant	Exon 2 of 3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.82G>T (p.A28S) alteration is located in exon 2 (coding exon 2) of the DNAJB13 gene. This alteration results from a G to T substitution at nucleotide position 82, causing the alanine (A) at amino acid position 28 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	0.0013	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	L
PhyloP100		8.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.26
Sift	Benign	0.036	D
Sift4G	Uncertain	0.057	T
Polyphen		0.97	D
Vest4		0.79
MutPred		0.80		Gain of phosphorylation at A28 (P = 0.0134);
MVP		0.55
MPC		0.82
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.27
gMVP		0.55
Mutation Taster		=46/54	disease causing

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: rs1950819983; hg19: chr11-73669375; COSMIC: COSV100334479;