14-103457138-A-G

Variant names:

• chr14-103457138-A-G
• rs2273699
• NM_001128918.3:c.413-4A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001128918.3(MARK3):​c.413-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,572,776 control chromosomes in the GnomAD database, including 91,062 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 0.34 (8876 hom., cov: 33)
  • Exomes 𝑓: 0.33 (82186 hom.)
• Consequence: MARK3 NM_001128918.3 splice_region, intron
• Scores: Splicing: ADA: 0.00008239
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0430

Genes affected

MARK3 (HGNC:6897): (microtubule affinity regulating kinase 3) The protein encoded by this gene is activated by phosphorylation and in turn is involved in the phosphorylation of tau proteins MAP2 and MAP4. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 14-103457138-A-G is Benign according to our data. Variant chr14-103457138-A-G is described in ClinVar as [Benign]. Clinvar id is 1321158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARK3	NM_001128918.3	c.413-4A>G		splice_region_variant, intron_variant	Intron 5 of 17	ENST00000429436.7	NP_001122390.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARK3	ENST00000429436.7	c.413-4A>G		splice_region_variant, intron_variant	Intron 5 of 17	1	NM_001128918.3	ENSP00000411397.2

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50969 AN: 152036 Hom.: 8872 Cov.: 33

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.342

GnomAD3 exomes AF: 0.314 AC: 78038 AN: 248170 Hom.: 13210 AF XY: 0.323 AC XY: 43482 AN XY: 134700

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.435

Gnomad EAS exome AF: 0.126

Gnomad SAS exome AF: 0.346

Gnomad FIN exome AF: 0.295

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.335 AC: 475427 AN: 1420622 Hom.: 82186 Cov.: 24 AF XY: 0.337 AC XY: 239278 AN XY: 709194

Gnomad4 AFR exome AF: 0.347

Gnomad4 AMR exome AF: 0.209

Gnomad4 ASJ exome AF: 0.439

Gnomad4 EAS exome AF: 0.162

Gnomad4 SAS exome AF: 0.351

Gnomad4 FIN exome AF: 0.303

Gnomad4 NFE exome AF: 0.343

Gnomad4 OTH exome AF: 0.339

GnomAD4 genome AF: 0.335 AC: 50988 AN: 152154 Hom.: 8876 Cov.: 33 AF XY: 0.330 AC XY: 24556 AN XY: 74396

Gnomad4 AFR AF: 0.352

Gnomad4 AMR AF: 0.276

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.339

Gnomad4 FIN AF: 0.282

Gnomad4 NFE AF: 0.355

Gnomad4 OTH AF: 0.340

Alfa AF: 0.351 Hom.: 5916

Bravo AF: 0.333

Asia WGS AF: 0.226 AC: 788 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

MARK3-related disorder Benign:1

Oct 22, 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). -

Visual impairment and progressive phthisis bulbi Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.77
DANN	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000082
dbscSNV1_RF	Benign	0.030
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

Publications

LitVar

Other links and lift over

dbSNP: rs2273699; hg19: chr14-103923475; COSMIC: COSV53510982;