16-71849931-G-T

Position:

chr16-71849931-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001137675.4(ATXN1L):c.191G>T(p.Gly64Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,551,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ATXN1L
NM_001137675.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.48

Variant links:

Genes affected

ATXN1L (HGNC:33279): (ataxin 1 like) Predicted to enable DNA binding activity and RNA binding activity. Predicted to be involved in several processes, including learning or memory; regulation of transcription, DNA-templated; and social behavior. Predicted to act upstream of or within several processes, including lung alveolus development; negative regulation of transcription by RNA polymerase II; and positive regulation of hematopoietic stem cell proliferation. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ATXN1L links:

IST1 (HGNC:28977): (IST1 factor associated with ESCRT-III) This gene encodes a protein with MIT-interacting motifs that interacts with components of endosomal sorting complexes required for transport (ESCRT). ESCRT functions in vesicle budding, such as that which occurs during membrane abscission in cytokinesis. There is a pseudogene for this gene on chromosome 19. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2012]

IST1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.215107).

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATXN1L	NM_001137675.4 linkuse as main transcript	c.191G>T	p.Gly64Val	missense_variant	3/3	ENST00000427980.7	NP_001131147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ATXN1L	ENST00000427980.7 linkuse as main transcript	c.191G>T	p.Gly64Val	missense_variant	3/3	1	NM_001137675.4	ENSP00000415822	P1
ATXN1L	ENST00000683775.1 linkuse as main transcript	c.191G>T	p.Gly64Val	missense_variant	3/3			ENSP00000507897	P1
IST1	ENST00000568581.5 linkuse as main transcript	c.-16+1860G>T		intron_variant		5		ENSP00000456200
ATXN1L	ENST00000569119.1 linkuse as main transcript	n.119+1860G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000261

AC:

AN:

153288

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

81366

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000237

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000463

GnomAD4 exome

AF:

0.0000114

AC:

AN:

1398956

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

689918

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000199

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000649

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000444

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2023

The c.191G>T (p.G64V) alteration is located in exon 3 (coding exon 1) of the ATXN1L gene. This alteration results from a G to T substitution at nucleotide position 191, causing the glycine (G) at amino acid position 64 to be replaced by a valine (V). 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

0.097

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.0049

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.75

M_CAP

Benign

0.0058

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.7

REVEL

Benign

0.057

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.021

Polyphen

0.84

Vest4

0.29

MutPred

0.49

Gain of sheet (P = 0.0016);

MVP

0.49

ClinPred

0.13

GERP RS

5.4

Varity_R

0.26

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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