1-155045940-A-T

Variant names:

• chr1-155045940-A-T
• rs746947901
• NM_152494.4:c.1220A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_152494.4(DCST1):​c.1220A>T​(p.Asn407Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 0.0000048 (0 hom.)
• Consequence: DCST1 NM_152494.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.43

Genes affected

DCST1 (HGNC:26539): (DC-STAMP domain containing 1) This gene encodes a protein with a domain similar to one found in dendritic cells (PMID:11169400) which play a key role in antigen processing and display for immune responses. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

DCST1-AS1 (HGNC:41147): (DCST1 antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCST1	NM_152494.4	c.1220A>T	p.Asn407Ile	missense_variant	Exon 11 of 17	ENST00000295542.6	NP_689707.2
DCST1	NM_001143687.2	c.1145A>T	p.Asn382Ile	missense_variant	Exon 10 of 16		NP_001137159.1
DCST1-AS1	NR_040772.1	n.939+20T>A		intron_variant	Intron 3 of 3
DCST1-AS1	NR_040773.1	n.524+20T>A		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCST1	ENST00000295542.6	c.1220A>T	p.Asn407Ile	missense_variant	Exon 11 of 17	2	NM_152494.4	ENSP00000295542.2
DCST1	ENST00000525273.5	n.1295A>T		non_coding_transcript_exon_variant	Exon 11 of 15	2		ENSP00000433667.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251482 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1220A>T (p.N407I) alteration is located in exon 11 (coding exon 10) of the DCST1 gene. This alteration results from a A to T substitution at nucleotide position 1220, causing the asparagine (N) at amino acid position 407 to be replaced by an isoleucine (I). 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	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.0	M;.;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-8.1	D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.88		Loss of catalytic residue at N407 (P = 0.0024);.;Loss of catalytic residue at N407 (P = 0.0024);
MVP		0.79
MPC		0.63
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs746947901; hg19: chr1-155018416;