rs56380300

Variant names:

• chr9-127479900-A-G
• rs56380300
• NM_001005373.4:c.965A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001005373.4(LRSAM1):​c.965A>G​(p.Gln322Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,611,996 control chromosomes in the GnomAD database, including 42 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (39 hom.)
• Consequence: LRSAM1 NM_001005373.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 2.60
• Publications: 7 publications found

Genes affected

LRSAM1 (HGNC:25135): (leucine rich repeat and sterile alpha motif containing 1) This gene encodes a ring finger protein involved in a variety of functions, including regulation of signaling pathways and cell adhesion, mediation of self-ubiquitylation, and involvement in cargo sorting during receptor endocytosis. Mutations in this gene have been associated with Charcot-Marie-Tooth disease. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jan 2012]

LRSAM1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2P

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072479546).
• BP6: Variant 9-127479900-A-G is Benign according to our data. Variant chr9-127479900-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00338 (515/152322) while in subpopulation SAS AF = 0.00807 (39/4830). AF 95% confidence interval is 0.00607. There are 3 homozygotes in GnomAd4. There are 244 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005373.4. 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
	LRSAM1	NM_001005373.4	MANE Select	c.965A>G	p.Gln322Arg	missense	Exon 14 of 26	NP_001005373.1	Q6UWE0-1
	LRSAM1	NM_001005374.4		c.965A>G	p.Gln322Arg	missense	Exon 13 of 25	NP_001005374.1	Q6UWE0-1
	LRSAM1	NM_001384142.1		c.965A>G	p.Gln322Arg	missense	Exon 14 of 26	NP_001371071.1	Q6UWE0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRSAM1	ENST00000300417.11	TSL:1 MANE Select	c.965A>G	p.Gln322Arg	missense	Exon 14 of 26	ENSP00000300417.6	Q6UWE0-1
	LRSAM1	ENST00000373322.1	TSL:1	c.965A>G	p.Gln322Arg	missense	Exon 13 of 25	ENSP00000362419.1	Q6UWE0-1
	LRSAM1	ENST00000870574.1		c.965A>G	p.Gln322Arg	missense	Exon 14 of 26	ENSP00000540633.1

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 516 AN: 152204 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00412

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00384 AC: 953 AN: 248064 AF XY: 0.00424

Gnomad AFR exome AF: 0.000647

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00691

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00406

Gnomad NFE exome AF: 0.00408

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00506 AC: 7385 AN: 1459674 Hom.: 39 Cov.: 35 AF XY: 0.00518 AC XY: 3759 AN XY: 726204

African (AFR) AF: 0.000747 AC: 25 AN: 33446

American (AMR) AF: 0.00146 AC: 65 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00731 AC: 191 AN: 26126

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39668

South Asian (SAS) AF: 0.00831 AC: 716 AN: 86172

European-Finnish (FIN) AF: 0.00422 AC: 223 AN: 52872

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5756

European-Non Finnish (NFE) AF: 0.00527 AC: 5858 AN: 1110728

Other (OTH) AF: 0.00481 AC: 290 AN: 60238

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152322 Hom.: 3 Cov.: 32 AF XY: 0.00328 AC XY: 244 AN XY: 74480

African (AFR) AF: 0.00111 AC: 46 AN: 41576

American (AMR) AF: 0.00529 AC: 81 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00807 AC: 39 AN: 4830

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00413 AC: 281 AN: 68030

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00413 Hom.: 2

Bravo AF: 0.00306

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00367 AC: 445

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00385

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	Charcot-Marie-Tooth disease axonal type 2P (4)
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.077
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.062
Sift	Benign	0.67	T
Sift4G	Benign	0.33	T
Polyphen		0.0010	B
Vest4		0.079
MVP		0.55
MPC		0.18
ClinPred		0.014	T
GERP RS		3.4
Varity_R		0.10
gMVP		0.17
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs56380300; hg19: chr9-130242179;