chr9-127496101-C-T

Variant names:

• chr9-127496101-C-T
• rs75171318
• NM_001005373.4:c.1830+6C>T

Variant summary

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

The ENST00000300417.11(LRSAM1):​c.1830+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,607,800 control chromosomes in the GnomAD database, including 681 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (50 hom., cov: 33)
  • Exomes 𝑓: 0.027 (631 hom.)
• Consequence: LRSAM1 ENST00000300417.11 splice_region, intron
• Scores: Splicing: ADA: 0.00001263
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.598
• 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: 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 (BayesDel_noAF=-0.84).
• BP6: Variant 9-127496101-C-T is Benign according to our data. Variant chr9-127496101-C-T is described in ClinVar as Benign. ClinVar VariationId is 241837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0182 (2779/152368) while in subpopulation NFE AF = 0.0269 (1833/68032). AF 95% confidence interval is 0.0259. There are 50 homozygotes in GnomAd4. There are 1360 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000300417.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRSAM1	NM_001005373.4	MANE Select	c.1830+6C>T		splice_region intron	N/A	NP_001005373.1
	LRSAM1	NM_001005374.4		c.1830+6C>T		splice_region intron	N/A	NP_001005374.1
	LRSAM1	NM_001384142.1		c.1830+6C>T		splice_region intron	N/A	NP_001371071.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRSAM1	ENST00000300417.11	TSL:1 MANE Select	c.1830+6C>T		splice_region intron	N/A	ENSP00000300417.6
	LRSAM1	ENST00000373322.1	TSL:1	c.1830+6C>T		splice_region intron	N/A	ENSP00000362419.1
	LRSAM1	ENST00000676170.1		c.1911+6C>T		splice_region intron	N/A	ENSP00000502177.1

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2777 AN: 152250 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.0282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0269

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0177 AC: 4349 AN: 245050 AF XY: 0.0178

Gnomad AFR exome AF: 0.00514

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0284

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0228

GnomAD4 exome AF: 0.0268 AC: 38976 AN: 1455432 Hom.: 631 Cov.: 32 AF XY: 0.0260 AC XY: 18802 AN XY: 724220

African (AFR) AF: 0.00463 AC: 155 AN: 33474

American (AMR) AF: 0.0111 AC: 495 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 425 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00732 AC: 631 AN: 86224

European-Finnish (FIN) AF: 0.0267 AC: 1260 AN: 47174

Middle Eastern (MID) AF: 0.0134 AC: 77 AN: 5760

European-Non Finnish (NFE) AF: 0.0307 AC: 34163 AN: 1111920

Other (OTH) AF: 0.0293 AC: 1769 AN: 60344

GnomAD4 genome AF: 0.0182 AC: 2779 AN: 152368 Hom.: 50 Cov.: 33 AF XY: 0.0183 AC XY: 1360 AN XY: 74514

African (AFR) AF: 0.00570 AC: 237 AN: 41590

American (AMR) AF: 0.0144 AC: 221 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00662 AC: 32 AN: 4832

European-Finnish (FIN) AF: 0.0282 AC: 300 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0269 AC: 1833 AN: 68032

Other (OTH) AF: 0.0165 AC: 35 AN: 2116

Alfa AF: 0.0214 Hom.: 15

Bravo AF: 0.0177

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0292

EpiControl AF: 0.0274

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.9
DANN	Benign	0.78
PhyloP100		-0.60
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
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: rs75171318; hg19: chr9-130258380;