14-103451987-A-T

Variant names:

• chr14-103451987-A-T
• rs572627741
• NM_001128918.3:c.412+4A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_001128918.3(MARK3):​c.412+4A>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000138 in 1,599,376 control chromosomes in the GnomAD database, including 1 homozygotes. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000015 (1 hom.)
• Consequence: MARK3 NM_001128918.3 splice_region, intron
• Scores: Splicing: ADA: 0.9985
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 6.91
• Publications: 1 publications found

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]

MARK3 Gene-Disease associations (from GenCC):

• visual impairment and progressive phthisis bulbi

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 14-103451987-A-T is Benign according to our data. Variant chr14-103451987-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3042616.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128918.3. 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
	MARK3	NM_001128918.3	MANE Select	c.412+4A>T		splice_region intron	N/A	NP_001122390.2	P27448-5
	MARK3	NM_001128919.3		c.412+4A>T		splice_region intron	N/A	NP_001122391.2	P27448-4
	MARK3	NM_001437366.1		c.358+4A>T		splice_region intron	N/A	NP_001424295.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARK3	ENST00000429436.7	TSL:1 MANE Select	c.412+4A>T		splice_region intron	N/A	ENSP00000411397.2	P27448-5
	MARK3	ENST00000556744.2	TSL:1	c.412+4A>T		splice_region intron	N/A	ENSP00000451623.2	H0YJI9
	MARK3	ENST00000416682.6	TSL:1	c.412+4A>T		splice_region intron	N/A	ENSP00000408092.2	P27448-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000145 AC: 21 AN: 1447120 Hom.: 1 Cov.: 27 AF XY: 0.0000194 AC XY: 14 AN XY: 720770

African (AFR) AF: 0.0000908 AC: 3 AN: 33036

American (AMR) AF: 0.00 AC: 0 AN: 43934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85292

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53246

Middle Eastern (MID) AF: 0.00283 AC: 16 AN: 5662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100520

Other (OTH) AF: 0.0000167 AC: 1 AN: 59884

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152256 Hom.: 0 Cov.: 30 AF XY: 0.0000134 AC XY: 1 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	MARK3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.19	T
MetaRNN	Uncertain	0.55	D
PhyloP100		6.9
PROVEAN	Uncertain	-3.0	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
MVP		0.58
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.010		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: rs572627741; hg19: chr14-103918324;