3-124446759-A-T

Variant names:

• chr3-124446759-A-T
• rs77701768
• NM_001388419.1:c.3430-4A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001388419.1(KALRN):​c.3430-4A>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 0.0028 in 1,614,068 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (56 hom.)
• Consequence: KALRN NM_001388419.1 splice_region, intron
• Scores: Splicing: ADA: 0.0005052
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.394
• Publications: 0 publications found

Genes affected

KALRN (HGNC:4814): (kalirin RhoGEF kinase) Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein that interacts with the huntingtin-associated protein 1, which is a huntingtin binding protein that may function in vesicle trafficking. [provided by RefSeq, Apr 2016]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 3-124446759-A-T is Benign according to our data. Variant chr3-124446759-A-T is described in ClinVar as [Benign]. Clinvar id is 3037337.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1	c.3430-4A>T		splice_region_variant, intron_variant	Intron 20 of 59	ENST00000682506.1	NP_001375348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KALRN	ENST00000682506.1	c.3430-4A>T		splice_region_variant, intron_variant	Intron 20 of 59		NM_001388419.1	ENSP00000508359.1

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2290 AN: 152150 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.0513

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00870

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: 0.000118

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00382 AC: 960 AN: 251222 AF XY: 0.00278

Gnomad AFR exome AF: 0.0527

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00152 AC: 2228 AN: 1461800 Hom.: 56 Cov.: 31 AF XY: 0.00124 AC XY: 901 AN XY: 727200

African (AFR) AF: 0.0550 AC: 1840 AN: 33474

American (AMR) AF: 0.00297 AC: 133 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111956

Other (OTH) AF: 0.00333 AC: 201 AN: 60392

GnomAD4 genome AF: 0.0151 AC: 2293 AN: 152268 Hom.: 47 Cov.: 32 AF XY: 0.0142 AC XY: 1060 AN XY: 74446

African (AFR) AF: 0.0512 AC: 2127 AN: 41528

American (AMR) AF: 0.00869 AC: 133 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.0171

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KALRN-related disorder Benign:1

May 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.7
DANN	Benign	0.67
PhyloP100		0.39
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00051
dbscSNV1_RF	Benign	0.014

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs77701768; hg19: chr3-124165606; COSMIC: COSV53778984;