NM_001382309.1:c.812G>A

Variant names:

• chr17-44194600-C-T
• rs566105744
• NM_001382309.1:c.812G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001382309.1(ATXN7L3):​c.812G>A​(p.Arg271Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: ATXN7L3 NM_001382309.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.78
• Publications: 2 publications found

Genes affected

ATXN7L3 (HGNC:25416): (ataxin 7 like 3) Enables nuclear receptor coactivator activity. Involved in histone deubiquitination; histone monoubiquitination; and positive regulation of transcription, DNA-templated. Located in nucleus. Part of DUBm complex and SAGA complex. [provided by Alliance of Genome Resources, Apr 2022]

ATXN7L3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18842563).
• BS2: High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382309.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7L3	NM_001382309.1	MANE Select	c.812G>A	p.Arg271Gln	missense	Exon 12 of 13	NP_001369238.1	Q14CW9-1
	ATXN7L3	NM_001382316.1		c.869G>A	p.Arg290Gln	missense	Exon 12 of 13	NP_001369245.1
	ATXN7L3	NM_001382308.1		c.833G>A	p.Arg278Gln	missense	Exon 12 of 13	NP_001369237.1	Q14CW9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7L3	ENST00000587097.6	TSL:5 MANE Select	c.812G>A	p.Arg271Gln	missense	Exon 12 of 13	ENSP00000465614.2	Q14CW9-1
	ATXN7L3	ENST00000454077.6	TSL:1	c.833G>A	p.Arg278Gln	missense	Exon 11 of 12	ENSP00000397259.1	Q14CW9-2
	ATXN7L3	ENST00000389384.8	TSL:1	c.812G>A	p.Arg271Gln	missense	Exon 11 of 12	ENSP00000374035.3	Q14CW9-1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 249088 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461660 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727122

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111996

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74456

African (AFR) AF: 0.0000241 AC: 1 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.071	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.75	N
PhyloP100		6.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.18
Sift	Benign	0.033	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.58
MutPred		0.29		Loss of phosphorylation at S270 (P = 0.1277)
MVP		0.42
MPC		1.2
ClinPred		0.29	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.46
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs566105744; hg19: chr17-42271968;