14-103475055-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001128918.3(MARK3):c.1327A>G(p.Ser443Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00799 in 1,614,142 control chromosomes in the GnomAD database, including 949 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.044 (512 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (437 hom.)
• Consequence: MARK3 NM_001128918.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.09

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014868975).
• BP6: Variant 14-103475055-A-G is Benign according to our data. Variant chr14-103475055-A-G is described in ClinVar as [Benign]. Clinvar id is 3056411.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARK3	NM_001128918.3	c.1327A>G	p.Ser443Gly	missense_variant	13/18	ENST00000429436.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARK3	ENST00000429436.7	c.1327A>G	p.Ser443Gly	missense_variant	13/18	1	NM_001128918.3	P1

Frequencies

GnomAD3 genomes AF: 0.0436 AC: 6636 AN: 152198 Hom.: 510 Cov.: 33

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

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: 0.000338

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.0108 AC: 2691 AN: 249506 Hom.: 205 AF XY: 0.00792 AC XY: 1072 AN XY: 135380

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.00678

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00427 AC: 6245 AN: 1461826 Hom.: 437 Cov.: 31 AF XY: 0.00363 AC XY: 2642 AN XY: 727216

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.00774

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000836

Gnomad4 OTH exome AF: 0.00947

GnomAD4 genome AF: 0.0437 AC: 6653 AN: 152316 Hom.: 512 Cov.: 33 AF XY: 0.0415 AC XY: 3094 AN XY: 74498

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.0134

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.00928 Hom.: 162

Bravo AF: 0.0494

ESP6500AA AF: 0.144 AC: 577

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0133 AC: 1608

Asia WGS AF: 0.00895 AC: 32 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MARK3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 30, 2019

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
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	15
Dann	Uncertain	0.99
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0015	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.042	P;P;P;P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N
REVEL	Benign	0.064
Sift	Benign	0.24	T;T;T;T;T;T;T;T
Sift4G	Benign	0.41	T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;B;B;B;B;.;.
Vest4		0.043
MPC		0.21
ClinPred		0.0057	T
GERP RS		2.0
Varity_R		0.14
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs56305318; hg19: chr14-103941392; COSMIC: COSV53510341; COSMIC: COSV53510341;