rs3219173

Variant names:

• chr2-201701404-C-T
• rs3219173
• NM_020919.4:c.*447G>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.*447G>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 0.0103 in 159,680 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: ALS2 NM_020919.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.05
• Publications: 3 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=-0.52).
• BP6: Variant 2-201701404-C-T is Benign according to our data. Variant chr2-201701404-C-T is described in ClinVar as Benign. ClinVar VariationId is 333578.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1635/152240) while in subpopulation AFR AF = 0.0366 (1521/41524). AF 95% confidence interval is 0.0351. There are 30 homozygotes in GnomAd4. There are 766 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.*447G>A		3_prime_UTR	Exon 34 of 34	NP_065970.2
	ALS2	NM_001410975.1		c.*447G>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.*447G>A		3_prime_UTR	Exon 34 of 34	ENSP00000264276.6	Q96Q42-1
	ALS2	ENST00000680497.1		c.*447G>A		3_prime_UTR	Exon 34 of 34	ENSP00000505954.1	A0A7P0Z4F3
	ALS2	ENST00000905985.1		c.*447G>A		3_prime_UTR	Exon 35 of 35	ENSP00000576044.1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1634 AN: 152122 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.00108 AC: 8 AN: 7440 Hom.: 0 Cov.: 0 AF XY: 0.000997 AC XY: 4 AN XY: 4012

African (AFR) AF: 0.0526 AC: 4 AN: 76

American (AMR) AF: 0.00162 AC: 2 AN: 1238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 102

East Asian (EAS) AF: 0.00 AC: 0 AN: 386

South Asian (SAS) AF: 0.00 AC: 0 AN: 740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.000247 AC: 1 AN: 4054

Other (OTH) AF: 0.00338 AC: 1 AN: 296

GnomAD4 genome AF: 0.0107 AC: 1635 AN: 152240 Hom.: 30 Cov.: 32 AF XY: 0.0103 AC XY: 766 AN XY: 74440

African (AFR) AF: 0.0366 AC: 1521 AN: 41524

American (AMR) AF: 0.00503 AC: 77 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

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: 0.000221 AC: 15 AN: 68012

Other (OTH) AF: 0.0104 AC: 22 AN: 2108

Alfa AF: 0.00742 Hom.: 11

Bravo AF: 0.0122

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.52
CADD	Benign	15
DANN	Benign	0.76
PhyloP100		1.1
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: rs3219173; hg19: chr2-202566127;