rs779873656

Variant names:

• chr9-127461226-C-A
• rs779873656
• NM_001005373.4:c.375C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-127461226-C-A
• chr9-127461226-C-T
• chr9-127461226-C-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001005373.4(LRSAM1):​c.375C>A​(p.Asn125Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,612,246 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Synonymous variant affecting the same amino acid position (i.e. N125N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: LRSAM1 NM_001005373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94
• Publications: 1 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: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13448179).

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.375C>A	p.Asn125Lys	missense	Exon 8 of 26	NP_001005373.1	Q6UWE0-1
	LRSAM1	NM_001005374.4		c.375C>A	p.Asn125Lys	missense	Exon 7 of 25	NP_001005374.1	Q6UWE0-1
	LRSAM1	NM_001384142.1		c.375C>A	p.Asn125Lys	missense	Exon 8 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.375C>A	p.Asn125Lys	missense	Exon 8 of 26	ENSP00000300417.6	Q6UWE0-1
	LRSAM1	ENST00000373322.1	TSL:1	c.375C>A	p.Asn125Lys	missense	Exon 7 of 25	ENSP00000362419.1	Q6UWE0-1
	LRSAM1	ENST00000870574.1		c.375C>A	p.Asn125Lys	missense	Exon 8 of 26	ENSP00000540633.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152230 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251494 AF XY: 0.0000589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1460016 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726286

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.000381 AC: 17 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110714

Other (OTH) AF: 0.0000332 AC: 2 AN: 60258

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152230 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.000785 AC: 12 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000128

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease axonal type 2P (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.96	L
PhyloP100		1.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.15
Sift	Benign	0.38	T
Sift4G	Benign	0.18	T
Polyphen		0.22	B
Vest4		0.28
MutPred		0.42		Gain of methylation at N125 (P = 0.0226)
MVP		0.41
MPC		0.20
ClinPred		0.12	T
GERP RS		6.2
Varity_R		0.056
gMVP		0.17
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs779873656; hg19: chr9-130223505;