12-74538323-C-G

Variant names:

• chr12-74538323-C-G
• rs754986939
• NM_001136262.2:c.211C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001136262.2(ATXN7L3B):​c.211C>G​(p.Arg71Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R71C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ATXN7L3B NM_001136262.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0510
• Publications: 0 publications found

Genes affected

ATXN7L3B (HGNC:37931): (ataxin 7 like 3B) Involved in regulation of gene expression. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000257386 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1678764).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136262.2. 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
	ATXN7L3B	NM_001136262.2	MANE Select	c.211C>G	p.Arg71Gly	missense	Exon 1 of 1	NP_001129734.1	Q96GX2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN7L3B	ENST00000519948.4	TSL:6 MANE Select	c.211C>G	p.Arg71Gly	missense	Exon 1 of 1	ENSP00000430000.2	Q96GX2
	ENSG00000257386	ENST00000550926.1	TSL:3	n.197G>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1400976 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 691150

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31630

American (AMR) AF: 0.00 AC: 0 AN: 35790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25198

East Asian (EAS) AF: 0.00 AC: 0 AN: 35792

South Asian (SAS) AF: 0.00 AC: 0 AN: 79288

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079872

Other (OTH) AF: 0.00 AC: 0 AN: 58158

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.051
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.036	D
Polyphen		0.86	P
Vest4		0.18
MutPred		0.31		Gain of loop (P = 0.0312)
MVP		0.099
MPC		0.46
ClinPred		0.78	D
GERP RS		4.1
PromoterAI		0.081	Neutral
Varity_R		0.42
gMVP		0.29
Mutation Taster		=88/12	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: rs754986939; hg19: chr12-74932103;