5-150715585-T-G

Position:

• chr5-150715585-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016221.4(DCTN4):​c.1149A>C​(p.Gln383His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DCTN4 NM_016221.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.113

Genes affected

DCTN4 (HGNC:15518): (dynactin subunit 4) Enables protein N-terminus binding activity. Located in centrosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCTN4	NM_016221.4	c.1149A>C	p.Gln383His	missense_variant	12/13	ENST00000447998.7	NP_057305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCTN4	ENST00000447998.7	c.1149A>C	p.Gln383His	missense_variant	12/13	1	NM_016221.4	ENSP00000416968.2
DCTN4	ENST00000446090.6	c.1170A>C	p.Gln390His	missense_variant	13/14	1		ENSP00000414906.2
DCTN4	ENST00000424236.5	c.978A>C	p.Gln326His	missense_variant	12/13	2		ENSP00000411251.1
DCTN4	ENST00000627368.2	c.*946A>C		3_prime_UTR_variant	14/15	5		ENSP00000487323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461836 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2024

The c.1170A>C (p.Q390H) alteration is located in exon 13 (coding exon 13) of the DCTN4 gene. This alteration results from a A to C substitution at nucleotide position 1170, causing the glutamine (Q) at amino acid position 390 to be replaced by a histidine (H). 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	0.25
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.022	T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.49	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.41	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.88	P;.;P
Vest4		0.58
MutPred		0.52		Loss of solvent accessibility (P = 0.0238);.;.;
MVP		0.33
MPC		0.69
ClinPred		0.25	T
GERP RS		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.62

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: rs139144865; hg19: chr5-150095147;