chr1-6639948-T-C

Variant names:

• chr1-6639948-T-C
• rs1252950956
• NM_018198.4:c.1207A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018198.4(DNAJC11):​c.1207A>G​(p.Met403Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M403R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: DNAJC11 NM_018198.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

Genes affected

DNAJC11 (HGNC:25570): (DnaJ heat shock protein family (Hsp40) member C11) Involved in cristae formation. Located in mitochondrial outer membrane and nuclear speck. Part of MIB complex. Colocalizes with MICOS complex and SAM complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061849505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC11	NM_018198.4	c.1207A>G	p.Met403Val	missense_variant	Exon 11 of 16	ENST00000377577.10	NP_060668.2
DNAJC11	XM_047424842.1	c.937A>G	p.Met313Val	missense_variant	Exon 9 of 14		XP_047280798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC11	ENST00000377577.10	c.1207A>G	p.Met403Val	missense_variant	Exon 11 of 16	1	NM_018198.4	ENSP00000366800.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251326 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135870

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1207A>G (p.M403V) alteration is located in exon 11 (coding exon 11) of the DNAJC11 gene. This alteration results from a A to G substitution at nucleotide position 1207, causing the methionine (M) at amino acid position 403 to be replaced by a valine (V). 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	0.064
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.5
DANN	Benign	0.77
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.11	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.047
Sift	Benign	0.93	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.43		Gain of sheet (P = 0.0827);
MVP		0.10
MPC		0.49
ClinPred		0.0099	T
GERP RS		2.4
Varity_R		0.031
gMVP		0.48

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: rs1252950956; hg19: chr1-6700008;