16-84479954-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_020947.4(MEAK7):c.1330C>T(p.Arg444Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00323 in 1,609,612 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R444H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (16 hom.)
• Consequence: MEAK7 NM_020947.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.62

Genes affected

MEAK7 (HGNC:29325): (MTOR associated protein, eak-7 homolog) Involved in several processes, including TOR signaling; positive regulation of protein localization to lysosome; and response to insulin. Located in cytosol; lysosomal membrane; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069999397).
• BP6: Variant 16-84479954-G-A is Benign according to our data. Variant chr16-84479954-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 778506.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEAK7	NM_020947.4	c.1330C>T	p.Arg444Cys	missense_variant	8/8	ENST00000343629.11
MEAK7	XM_005256075.3	c.1330C>T	p.Arg444Cys	missense_variant	9/9
MEAK7	XM_017023511.2	c.1330C>T	p.Arg444Cys	missense_variant	8/8
MEAK7	XM_047434410.1	c.1330C>T	p.Arg444Cys	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEAK7	ENST00000343629.11	c.1330C>T	p.Arg444Cys	missense_variant	8/8	1	NM_020947.4	P1
MEAK7	ENST00000566995.5	c.*744C>T		3_prime_UTR_variant, NMD_transcript_variant	9/9	5
MEAK7	ENST00000570036.5	c.*1385C>T		3_prime_UTR_variant, NMD_transcript_variant	9/9	2

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 408 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00439

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00255 AC: 635 AN: 249320 Hom.: 2 AF XY: 0.00266 AC XY: 359 AN XY: 134750

Gnomad AFR exome AF: 0.000869

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.000231

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00426

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00328 AC: 4783 AN: 1457266 Hom.: 16 Cov.: 31 AF XY: 0.00324 AC XY: 2346 AN XY: 724684

Gnomad4 AFR exome AF: 0.000870

Gnomad4 AMR exome AF: 0.00213

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.0000759

Gnomad4 SAS exome AF: 0.000245

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.00388

Gnomad4 OTH exome AF: 0.00288

GnomAD4 genome AF: 0.00268 AC: 408 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.00272 AC XY: 203 AN XY: 74496

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00103

Gnomad4 NFE AF: 0.00440

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00372 Hom.: 6

Bravo AF: 0.00277

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00237 AC: 288

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00519

EpiControl AF: 0.00405

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	16
Dann	Benign	0.91
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.022
Sift	Benign	0.078	T
Sift4G	Benign	0.20	T
Polyphen		0.080	B
Vest4		0.14
MVP		0.13
MPC		0.0017
ClinPred		0.024	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.40

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: rs113746582; hg19: chr16-84513560; COSMIC: COSV59143920;