rs144613080

Variant names:

• chr2-201701472-A-T
• rs144613080
• NM_020919.4:c.*379T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020919.4(ALS2):​c.*379T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00817 in 174,906 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0092 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: ALS2 NM_020919.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.934
• Publications: 0 publications found

Genes affected

ALS2 (HGNC:443): (alsin Rho guanine nucleotide exchange factor ALS2) The protein encoded by this gene contains an ATS1/RCC1-like domain, a RhoGEF domain, and a vacuolar protein sorting 9 (VPS9) domain, all of which are guanine-nucleotide exchange factors that activate members of the Ras superfamily of GTPases. The protein functions as a guanine nucleotide exchange factor for the small GTPase RAB5. The protein localizes with RAB5 on early endosomal compartments, and functions as a modulator for endosomal dynamics. Mutations in this gene result in several forms of juvenile lateral sclerosis and infantile-onset ascending spastic paralysis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ALS2 Gene-Disease associations (from GenCC):

• ALS2-related motor neuron disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• amyotrophic lateral sclerosis type 2, juvenile

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• infantile-onset ascending hereditary spastic paralysis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• juvenile primary lateral sclerosis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-201701472-A-T is Benign according to our data. Variant chr2-201701472-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 333579.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00923 (1406/152266) while in subpopulation AFR AF = 0.0324 (1348/41548). AF 95% confidence interval is 0.031. There are 20 homozygotes in GnomAd4. There are 668 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020919.4. 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
	ALS2	NM_020919.4	MANE Select	c.*379T>A		3_prime_UTR	Exon 34 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.*379T>A		3_prime_UTR	Exon 34 of 34	NP_001397904.1	A0A7P0T8F3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALS2	ENST00000264276.11	TSL:1 MANE Select	c.*379T>A		3_prime_UTR	Exon 34 of 34	ENSP00000264276.6	Q96Q42-1
	ALS2	ENST00000680497.1		c.*379T>A		3_prime_UTR	Exon 34 of 34	ENSP00000505954.1	A0A7P0Z4F3
	ALS2	ENST00000905985.1		c.*379T>A		3_prime_UTR	Exon 35 of 35	ENSP00000576044.1

Frequencies

GnomAD3 genomes AF: 0.00923 AC: 1404 AN: 152148 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00102 AC: 23 AN: 22640 Hom.: 0 Cov.: 0 AF XY: 0.00110 AC XY: 13 AN XY: 11868

African (AFR) AF: 0.0316 AC: 15 AN: 474

American (AMR) AF: 0.00257 AC: 6 AN: 2336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 544

East Asian (EAS) AF: 0.00 AC: 0 AN: 1434

South Asian (SAS) AF: 0.00 AC: 0 AN: 2280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 66

European-Non Finnish (NFE) AF: 0.0000749 AC: 1 AN: 13354

Other (OTH) AF: 0.000831 AC: 1 AN: 1204

GnomAD4 genome AF: 0.00923 AC: 1406 AN: 152266 Hom.: 20 Cov.: 32 AF XY: 0.00897 AC XY: 668 AN XY: 74456

African (AFR) AF: 0.0324 AC: 1348 AN: 41548

American (AMR) AF: 0.00242 AC: 37 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68008

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00728 Hom.: 3

Bravo AF: 0.0104

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ALS2-related disorder (1)
-	-	1	Amyotrophic lateral sclerosis type 2, juvenile (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.7
DANN	Benign	0.61
PhyloP100		0.93
Mutation Taster		=100/0	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: rs144613080; hg19: chr2-202566195;