Genetic Variant NM_004896.5:c.*449C>T (chr10-69171718-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004896.5(VPS26A):c.*449C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 154,168 control chromosomes in the GnomAD database, including 4,689 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 4603 hom., cov: 32)

Exomes 𝑓: 0.27 ( 86 hom. )

Consequence

VPS26A
NM_004896.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.411

Publications

100 publications found

Variant links:

Genes affected

VPS26A (HGNC:12711): (VPS26 retromer complex component A) This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

VPS26A links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004896.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
VPS26A	NM_004896.5	MANE Select	c.*449C>T	3_prime_UTR	Exon 9 of 9	NP_004887.2
VPS26A	NM_001318944.2		c.*449C>T	3_prime_UTR	Exon 10 of 10	NP_001305873.1
VPS26A	NM_001318945.2		c.*449C>T	3_prime_UTR	Exon 10 of 10	NP_001305874.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VPS26A	ENST00000263559.11	TSL:1 MANE Select	c.*449C>T	3_prime_UTR	Exon 9 of 9	ENSP00000263559.6	O75436-1
VPS26A	ENST00000940629.1		c.*449C>T	splice_region	Exon 9 of 9	ENSP00000610688.1
VPS26A	ENST00000858434.1		c.*449C>T	splice_region	Exon 8 of 8	ENSP00000528493.1

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33473

AN:

151990

Hom.:

4601

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0573

Gnomad AMI

AF:

0.303

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.241

Gnomad EAS

AF:

0.115

Gnomad SAS

AF:

0.251

Gnomad FIN

AF:

0.289

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.307

Gnomad OTH

AF:

0.221

GnomAD4 exome

AF:

0.268

AC:

552

AN:

2060

Hom.:

Cov.:

AF XY:

0.262

AC XY:

289

AN XY:

1102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.0909

AC:

AN:

East Asian (EAS)

AF:

0.0500

AC:

AN:

South Asian (SAS)

AF:

0.181

AC:

AN:

116

European-Finnish (FIN)

AF:

0.306

AC:

152

AN:

496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.276

AC:

357

AN:

1292

Other (OTH)

AF:

0.188

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.220

AC:

33476

AN:

152108

Hom.:

4603

Cov.:

AF XY:

0.220

AC XY:

16350

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0571

AC:

2370

AN:

41526

American (AMR)

AF:

0.246

AC:

3750

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.241

AC:

836

AN:

3472

East Asian (EAS)

AF:

0.115

AC:

597

AN:

5186

South Asian (SAS)

AF:

0.251

AC:

1210

AN:

4830

European-Finnish (FIN)

AF:

0.289

AC:

3044

AN:

10548

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.307

AC:

20866

AN:

67964

Other (OTH)

AF:

0.218

AC:

460

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1277

2554

3831

5108

6385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

364

728

1092

1456

1820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.278

Hom.:

28606

Bravo

AF:

0.207

Asia WGS

AF:

0.167

AC:

580

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

8.0

(source)

DANN

Benign

0.52

PhyloP100

0.41

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over