13-106567726-A-C

Variant names:

• chr13-106567726-A-C
• rs1842071975
• NM_018011.4:c.194T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018011.4(ARGLU1):​c.194T>G​(p.Val65Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 147,950 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARGLU1 NM_018011.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.429
• Publications: 0 publications found

Genes affected

ARGLU1 (HGNC:25482): (arginine and glutamate rich 1) Enables cadherin binding activity. Located in cytosol; mitochondrion; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ARGLU1-DT (HGNC:43691): (ARGLU1 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0674102).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018011.4. 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
	ARGLU1	NM_018011.4	MANE Select	c.194T>G	p.Val65Gly	missense	Exon 1 of 4	NP_060481.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARGLU1	ENST00000400198.8	TSL:1 MANE Select	c.194T>G	p.Val65Gly	missense	Exon 1 of 4	ENSP00000383059.3	Q9NWB6-1
	ARGLU1	ENST00000952389.1		c.194T>G	p.Val65Gly	missense	Exon 1 of 5	ENSP00000622448.1
	ARGLU1	ENST00000868085.1		c.194T>G	p.Val65Gly	missense	Exon 1 of 4	ENSP00000538144.1

Frequencies

GnomAD3 genomes AF: 0.000122 AC: 18 AN: 147802 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000986

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000884

Gnomad SAS AF: 0.00117

Gnomad FIN AF: 0.000100

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000299

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000360 AC: 494 AN: 1371774 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 248 AN XY: 683850

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

African (AFR) AF: 0.000429 AC: 13 AN: 30336

American (AMR) AF: 0.000189 AC: 8 AN: 42384

Ashkenazi Jewish (ASJ) AF: 0.000930 AC: 21 AN: 22572

East Asian (EAS) AF: 0.000388 AC: 13 AN: 33544

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85308

European-Finnish (FIN) AF: 0.00526 AC: 227 AN: 43134

Middle Eastern (MID) AF: 0.000190 AC: 1 AN: 5266

European-Non Finnish (NFE) AF: 0.000169 AC: 178 AN: 1055222

Other (OTH) AF: 0.000555 AC: 30 AN: 54008

⚠️ 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 AF: 0.000122 AC: 18 AN: 147950 Hom.: 0 Cov.: 32 AF XY: 0.000111 AC XY: 8 AN XY: 72250

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

African (AFR) AF: 0.0000983 AC: 4 AN: 40672

American (AMR) AF: 0.000134 AC: 2 AN: 14904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.000885 AC: 4 AN: 4522

South Asian (SAS) AF: 0.00116 AC: 5 AN: 4300

European-Finnish (FIN) AF: 0.000100 AC: 1 AN: 9988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000299 AC: 2 AN: 66882

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	0.069
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Benign	0.85
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.43
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.050
Sift	Benign	0.47	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.26		Gain of relative solvent accessibility (P = 0.0023)
MVP		0.11
MPC		1.8
ClinPred		0.093	T
GERP RS		2.6
PromoterAI		-0.066	Neutral
Varity_R		0.054
gMVP		0.27
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: rs1842071975; hg19: chr13-107220074;