Genetic Variant NM_017552.4:c.3962C>T (chr2-23757534-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_017552.4(ATAD2B):c.3962C>T(p.Ser1321Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000439 in 1,593,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

ATAD2B
NM_017552.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.717

Variant links:

Genes affected

ATAD2B (HGNC:29230): (ATPase family AAA domain containing 2B) The protein encoded by this gene belongs to the AAA ATPase family. This family member includes an N-terminal bromodomain. It has been found to be localized to the nucleus, partly to replication sites, consistent with a chromatin-related function. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ATAD2B links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.047993004).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATAD2B	NM_017552.4 link	c.3962C>T	p.Ser1321Leu	missense_variant	Exon 25 of 28	ENST00000238789.10	NP_060022.2	Q9ULI0-1B3KWS5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATAD2B	ENST00000238789.10 link	c.3962C>T	p.Ser1321Leu	missense_variant	Exon 25 of 28	5	NM_017552.4	ENSP00000238789.5	Q9ULI0-1
ATAD2B	ENST00000381024.4 link	c.1787C>T	p.Ser596Leu	missense_variant	Exon 9 of 12	1		ENSP00000370412.4	H7BYF1
ATAD2B	ENST00000474583.5 link	n.3107C>T		non_coding_transcript_exon_variant	Exon 16 of 19	2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000390

AC:

AN:

230832

Hom.:

AF XY:

0.0000719

AC XY:

AN XY:

125258

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000335

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000594

Gnomad SAS exome

AF:

0.0000378

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000465

Gnomad OTH exome

AF:

0.000182

GnomAD4 exome

AF:

0.0000430

AC:

AN:

1441320

Hom.:

Cov.:

AF XY:

0.0000447

AC XY:

AN XY:

716374

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000252

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000487

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000498

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000762

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3962C>T (p.S1321L) alteration is located in exon 25 (coding exon 25) of the ATAD2B gene. This alteration results from a C to T substitution at nucleotide position 3962, causing the serine (S) at amino acid position 1321 to be replaced by a leucine (L). 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

0.068

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.67

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.29

M_CAP

Benign

0.051

MetaRNN

Benign

0.048

MetaSVM

Benign

-0.52

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.58

REVEL

Benign

0.17

Sift

Benign

0.72

Sift4G

Benign

0.48

Vest4

0.092

MVP

0.32

MPC

0.44

ClinPred

0.033

GERP RS

2.5

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over