rs10949483

Variant names:

• chr6-18122275-G-A
• rs10949483
• NM_198586.3:c.332C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-18122275-G-A
• chr6-18122275-G-C
• chr6-18122275-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_198586.3(NHLRC1):​c.332C>T​(p.Pro111Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,600,126 control chromosomes in the GnomAD database, including 122,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10019 hom., cov: 33)
  • Exomes 𝑓: 0.39 (112505 hom.)
• Consequence: NHLRC1 NM_198586.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.58
• Publications: 38 publications found

Genes affected

NHLRC1 (HGNC:21576): (NHL repeat containing E3 ubiquitin protein ligase 1) The protein encoded by this gene is a single subunit E3 ubiquitin ligase. Laforin is polyubiquitinated by the encoded protein. Defects in this intronless gene lead to an accumulation of laforin and onset of Lafora disease, also known as progressive myoclonic epilepsy type 2 (EPM2).[provided by RefSeq, Mar 2010]

NHLRC1 Gene-Disease associations (from GenCC):

• Lafora disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.49521 (below the threshold of 3.09). Trascript score misZ: -0.085446 (below the threshold of 3.09). GenCC associations: The gene is linked to Lafora disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0011947155).
• BP6: Variant 6-18122275-G-A is Benign according to our data. Variant chr6-18122275-G-A is described in ClinVar as Benign. ClinVar VariationId is 129767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198586.3. 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
	NHLRC1	NM_198586.3	MANE Select	c.332C>T	p.Pro111Leu	missense	Exon 1 of 1	NP_940988.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC1	ENST00000340650.6	TSL:6 MANE Select	c.332C>T	p.Pro111Leu	missense	Exon 1 of 1	ENSP00000345464.3	Q6VVB1

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53893 AN: 152020 Hom.: 10017 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.358

GnomAD2 exomes AF: 0.403 AC: 89747 AN: 222478 AF XY: 0.396

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.533

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.393

Gnomad FIN exome AF: 0.436

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.406

GnomAD4 exome AF: 0.392 AC: 567076 AN: 1447990 Hom.: 112505 Cov.: 56 AF XY: 0.390 AC XY: 281056 AN XY: 720376

African (AFR) AF: 0.234 AC: 7829 AN: 33424

American (AMR) AF: 0.519 AC: 22893 AN: 44122

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 9738 AN: 25990

East Asian (EAS) AF: 0.381 AC: 15082 AN: 39600

South Asian (SAS) AF: 0.336 AC: 28927 AN: 86082

European-Finnish (FIN) AF: 0.428 AC: 18358 AN: 42864

Middle Eastern (MID) AF: 0.374 AC: 2149 AN: 5750

European-Non Finnish (NFE) AF: 0.396 AC: 439220 AN: 1110000

Other (OTH) AF: 0.380 AC: 22880 AN: 60158

GnomAD4 genome AF: 0.354 AC: 53911 AN: 152136 Hom.: 10019 Cov.: 33 AF XY: 0.356 AC XY: 26449 AN XY: 74382

African (AFR) AF: 0.243 AC: 10110 AN: 41532

American (AMR) AF: 0.422 AC: 6455 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1251 AN: 3470

East Asian (EAS) AF: 0.373 AC: 1917 AN: 5144

South Asian (SAS) AF: 0.333 AC: 1604 AN: 4824

European-Finnish (FIN) AF: 0.417 AC: 4428 AN: 10606

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26797 AN: 67952

Other (OTH) AF: 0.358 AC: 755 AN: 2110

Alfa AF: 0.379 Hom.: 11148

Bravo AF: 0.353

TwinsUK AF: 0.399 AC: 1481

ALSPAC AF: 0.410 AC: 1579

ESP6500AA AF: 0.243 AC: 1051

ESP6500EA AF: 0.385 AC: 3258

ExAC AF: 0.386 AC: 45836

Asia WGS AF: 0.359 AC: 1245 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Lafora disease (5)
-	-	5	not specified (5)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0012	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	1.6	L
PhyloP100		1.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.33
Sift	Benign	0.032	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.16	B
Vest4		0.067
MPC		0.70
ClinPred		0.034	T
GERP RS		5.2
PromoterAI		-0.027	Neutral
Varity_R		0.13
gMVP		0.46
Mutation Taster		=93/7	polymorphism (auto)

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: rs10949483; hg19: chr6-18122506; COSMIC: COSV61481325;