chr9-127496037-C-T

Variant names:

• chr9-127496037-C-T
• rs139344911
• NM_001005373.4:c.1772C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001005373.4(LRSAM1):​c.1772C>T​(p.Ala591Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000763 in 1,612,204 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A591A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000076 (1 hom.)
• Consequence: LRSAM1 NM_001005373.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.69
• Publications: 2 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 -1 ACMG points.

• BP6: Variant 9-127496037-C-T is Benign according to our data. Variant chr9-127496037-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 365031.

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.1772C>T	p.Ala591Val	missense	Exon 23 of 26	NP_001005373.1	Q6UWE0-1
	LRSAM1	NM_001005374.4		c.1772C>T	p.Ala591Val	missense	Exon 22 of 25	NP_001005374.1	Q6UWE0-1
	LRSAM1	NM_001384142.1		c.1772C>T	p.Ala591Val	missense	Exon 23 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.1772C>T	p.Ala591Val	missense	Exon 23 of 26	ENSP00000300417.6	Q6UWE0-1
	LRSAM1	ENST00000373322.1	TSL:1	c.1772C>T	p.Ala591Val	missense	Exon 22 of 25	ENSP00000362419.1	Q6UWE0-1
	LRSAM1	ENST00000870574.1		c.1928C>T	p.Ala643Val	missense	Exon 23 of 26	ENSP00000540633.1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000157 AC: 39 AN: 248766 AF XY: 0.000163

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000760 AC: 111 AN: 1459988 Hom.: 1 Cov.: 32 AF XY: 0.0000799 AC XY: 58 AN XY: 726332

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00245 AC: 64 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111944

Other (OTH) AF: 0.000298 AC: 18 AN: 60358

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74360

African (AFR) AF: 0.000121 AC: 5 AN: 41452

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

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

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		6.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.15	T
Polyphen		0.99	D
Vest4		0.89
MutPred		0.57		Gain of phosphorylation at Y586 (P = 0.2419)
MVP		0.91
MPC		0.65
ClinPred		0.28	T
GERP RS		5.8
Varity_R		0.55
gMVP		0.37
Mutation Taster		=67/33	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: rs139344911; hg19: chr9-130258316;