Genetic Variant NM_022070.5:c.2780A>G (chr17-60046219-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022070.5(HEATR6):c.2780A>G(p.Asn927Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000187 in 1,604,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N927K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HEATR6
NM_022070.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03

Publications

0 publications found

Variant links:

Genes affected

HEATR6 (HGNC:24076): (HEAT repeat containing 6) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

HEATR6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022070.5. 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
	HEATR6	NM_022070.5	MANE Select	c.2780A>G	p.Asn927Ser	missense	Exon 19 of 20	NP_071353.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HEATR6	ENST00000184956.11	TSL:1 MANE Select	c.2780A>G	p.Asn927Ser	missense	Exon 19 of 20	ENSP00000184956.5	Q6AI08
HEATR6	ENST00000587003.5	TSL:1	n.*1551A>G		non_coding_transcript_exon	Exon 19 of 20	ENSP00000466192.1	K7ELR8
HEATR6	ENST00000587003.5	TSL:1	n.*1551A>G		3_prime_UTR	Exon 19 of 20	ENSP00000466192.1	K7ELR8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1452268

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722068

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32818

American (AMR)

AF:

0.00

AC:

AN:

42556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25718

East Asian (EAS)

AF:

0.00

AC:

AN:

39602

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107980

Other (OTH)

AF:

0.0000167

AC:

AN:

59930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.1

PhyloP100

4.0

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-4.4

REVEL

Benign

0.24

Sift

Benign

0.13

Sift4G

Benign

0.071

Polyphen

0.19

Vest4

0.55

MutPred

0.72

Gain of phosphorylation at N927 (P = 0.031)

MVP

0.76

MPC

0.12

ClinPred

0.97

GERP RS

4.3

Varity_R

0.27

gMVP

0.68

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over