1-78016018-T-C

Variant names:

• chr1-78016018-T-C
• NM_007034.5:c.785T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_007034.5(DNAJB4):​c.785T>C​(p.Leu262Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAJB4 NM_007034.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02
• Publications: 1 publications found

Genes affected

DNAJB4 (HGNC:14886): (DnaJ heat shock protein family (Hsp40) member B4) The protein encoded by this gene is a molecular chaperone, tumor suppressor, and member of the heat shock protein-40 family. The encoded protein binds the cell adhesion protein E-cadherin and targets it to the plasma membrane. This protein also binds incorrectly folded E-cadherin and targets it for endoplasmic reticulum-associated degradation. This gene is a strong tumor suppressor for colorectal carcinoma, and downregulation of it may serve as a good biomarker for predicting patient outcomes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

GIPC2 (HGNC:18177): (GIPC PDZ domain containing family member 2) Enables identical protein binding activity. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.2077 (below the threshold of 3.09). Trascript score misZ: 1.8136 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital myopathy 21 with early respiratory failure, congenital myopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant 1-78016018-T-C is Pathogenic according to our data. Variant chr1-78016018-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2499483.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007034.5. 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
	DNAJB4	NM_007034.5	MANE Select	c.785T>C	p.Leu262Ser	missense	Exon 3 of 3	NP_008965.2
	DNAJB4	NM_001317099.2		c.785T>C	p.Leu262Ser	missense	Exon 4 of 4	NP_001304028.1	Q9UDY4
	DNAJB4	NM_001317100.2		c.665T>C	p.Leu222Ser	missense	Exon 4 of 4	NP_001304029.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB4	ENST00000370763.6	TSL:1 MANE Select	c.785T>C	p.Leu262Ser	missense	Exon 3 of 3	ENSP00000359799.5	Q9UDY4
	DNAJB4	ENST00000867099.1		c.785T>C	p.Leu262Ser	missense	Exon 4 of 4	ENSP00000537158.1
	DNAJB4	ENST00000867100.1		c.785T>C	p.Leu262Ser	missense	Exon 4 of 4	ENSP00000537159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461240 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726880

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111662

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital myopathy 21 with early respiratory failure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		8.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.75		Loss of stability (P = 0.0496)
MVP		0.70
MPC		0.88
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.91
Mutation Taster		=47/53	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

hg19: chr1-78481702; COSMIC: COSV66132087; COSMIC: COSV66132087;