chr10-27170817-C-G

Variant names:

• chr10-27170817-C-G
• rs3802526
• NM_001172303.3:c.1858C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001172303.3(MASTL):​c.1858C>G​(p.Pro620Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0652 in 1,613,964 control chromosomes in the GnomAD database, including 4,616 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (474 hom., cov: 32)
  • Exomes 𝑓: 0.064 (4142 hom.)
• Consequence: MASTL NM_001172303.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.331
• Publications: 21 publications found

Genes affected

MASTL (HGNC:19042): (microtubule associated serine/threonine kinase like) This gene encodes a microtubule-associated serine/threonine kinase. Mutations at this locus have been associated with autosomal dominant thrombocytopenia, also known as thrombocytopenia-2. Alternatively spliced transcript variants have been described for this locus. [provided by RefSeq, Feb 2010]

ACBD5 (HGNC:23338): (acyl-CoA binding domain containing 5) This gene encodes a member of the acyl-Coenzyme A binding protein family, known to function in the transport and distribution of long chain acyl-Coenzyme A in cells. This gene may play a role in the differentiation of megakaryocytes and formation of platelets. A related protein in yeast is involved in autophagy of peroxisomes. A mutation in this gene has been associated with autosomal dominant thrombocytopenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACBD5 Gene-Disease associations (from GenCC):

• retinal dystrophy with leukodystrophy

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• acyl-CoA binding domain containing protein 5 deficiency

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017546713).
• BP6: Variant 10-27170817-C-G is Benign according to our data. Variant chr10-27170817-C-G is described in ClinVar as Benign. ClinVar VariationId is 262116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MASTL	NM_001172303.3	c.1858C>G	p.Pro620Ala	missense_variant	Exon 8 of 12	ENST00000375940.9	NP_001165774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MASTL	ENST00000375940.9	c.1858C>G	p.Pro620Ala	missense_variant	Exon 8 of 12	1	NM_001172303.3	ENSP00000365107.5

Frequencies

GnomAD3 genomes AF: 0.0730 AC: 11108 AN: 152078 Hom.: 474 Cov.: 32

Gnomad AFR AF: 0.0848

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0508

Gnomad ASJ AF: 0.0773

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0541

Gnomad OTH AF: 0.0531

GnomAD2 exomes AF: 0.0821 AC: 20620 AN: 251038 AF XY: 0.0842

Gnomad AFR exome AF: 0.0854

Gnomad AMR exome AF: 0.0657

Gnomad ASJ exome AF: 0.0729

Gnomad EAS exome AF: 0.149

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.0548

Gnomad OTH exome AF: 0.0675

GnomAD4 exome AF: 0.0644 AC: 94112 AN: 1461768 Hom.: 4142 Cov.: 34 AF XY: 0.0667 AC XY: 48502 AN XY: 727188

African (AFR) AF: 0.0869 AC: 2910 AN: 33478

American (AMR) AF: 0.0623 AC: 2785 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0735 AC: 1921 AN: 26132

East Asian (EAS) AF: 0.206 AC: 8162 AN: 39678

South Asian (SAS) AF: 0.144 AC: 12397 AN: 86256

European-Finnish (FIN) AF: 0.109 AC: 5809 AN: 53412

Middle Eastern (MID) AF: 0.0496 AC: 286 AN: 5768

European-Non Finnish (NFE) AF: 0.0502 AC: 55802 AN: 1111934

Other (OTH) AF: 0.0669 AC: 4040 AN: 60390

GnomAD4 genome AF: 0.0731 AC: 11124 AN: 152196 Hom.: 474 Cov.: 32 AF XY: 0.0772 AC XY: 5744 AN XY: 74408

African (AFR) AF: 0.0852 AC: 3539 AN: 41544

American (AMR) AF: 0.0507 AC: 775 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0773 AC: 268 AN: 3466

East Asian (EAS) AF: 0.160 AC: 827 AN: 5162

South Asian (SAS) AF: 0.156 AC: 752 AN: 4834

European-Finnish (FIN) AF: 0.108 AC: 1139 AN: 10584

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0541 AC: 3681 AN: 67996

Other (OTH) AF: 0.0530 AC: 112 AN: 2114

Alfa AF: 0.0597 Hom.: 279

Bravo AF: 0.0689

TwinsUK AF: 0.0539 AC: 200

ALSPAC AF: 0.0485 AC: 187

ESP6500AA AF: 0.0819 AC: 361

ESP6500EA AF: 0.0522 AC: 449

ExAC AF: 0.0840 AC: 10204

Asia WGS AF: 0.154 AC: 533 AN: 3478

EpiCase AF: 0.0528

EpiControl AF: 0.0499

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 27, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thrombocytopenia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.1
DANN	Benign	0.75
DEOGEN2	Benign	0.013	.;T;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.77	T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N;.
PhyloP100		0.33
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N;N;N;.
REVEL	Benign	0.063
Sift	Benign	0.18	T;T;T;.
Sift4G	Benign	0.49	T;T;T;T
Polyphen		0.29	B;B;B;.
Vest4		0.16
MPC		0.15
ClinPred		0.017	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.12
Mutation Taster		=98/2	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: rs3802526; hg19: chr10-27459746; COSMIC: COSV60909850;