rs2275687

Positions:

• chr1-236554626-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018072.6(HEATR1):​c.6050A>G​(p.Glu2017Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.658 in 1,610,758 control chromosomes in the GnomAD database, including 355,605 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.60 (28249 hom., cov: 31)
  • Exomes 𝑓: 0.66 (327356 hom.)
• Consequence: HEATR1 NM_018072.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.28

Genes affected

HEATR1 (HGNC:25517): (HEAT repeat containing 1) Enables RNA binding activity. Involved in positive regulation of rRNA processing and positive regulation of transcription by RNA polymerase I. Located in fibrillar center and mitochondrion. Implicated in pancreatic ductal carcinoma. Biomarker of glioblastoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.7085176E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEATR1	NM_018072.6	c.6050A>G	p.Glu2017Gly	missense_variant	42/45	ENST00000366582.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEATR1	ENST00000366582.8	c.6050A>G	p.Glu2017Gly	missense_variant	42/45	5	NM_018072.6	P1
HEATR1	ENST00000366581.6	c.5807A>G	p.Glu1936Gly	missense_variant	41/44	5

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90580 AN: 151828 Hom.: 28240 Cov.: 31

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.753

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.600

GnomAD3 exomes AF: 0.609 AC: 151815 AN: 249426 Hom.: 47732 AF XY: 0.609 AC XY: 82062 AN XY: 134704

Gnomad AFR exome AF: 0.435

Gnomad AMR exome AF: 0.531

Gnomad ASJ exome AF: 0.601

Gnomad EAS exome AF: 0.488

Gnomad SAS exome AF: 0.473

Gnomad FIN exome AF: 0.736

Gnomad NFE exome AF: 0.687

Gnomad OTH exome AF: 0.628

GnomAD4 exome AF: 0.665 AC: 969447 AN: 1458812 Hom.: 327356 Cov.: 38 AF XY: 0.659 AC XY: 478505 AN XY: 725620

Gnomad4 AFR exome AF: 0.431

Gnomad4 AMR exome AF: 0.531

Gnomad4 ASJ exome AF: 0.602

Gnomad4 EAS exome AF: 0.477

Gnomad4 SAS exome AF: 0.479

Gnomad4 FIN exome AF: 0.739

Gnomad4 NFE exome AF: 0.698

Gnomad4 OTH exome AF: 0.636

GnomAD4 genome AF: 0.596 AC: 90630 AN: 151946 Hom.: 28249 Cov.: 31 AF XY: 0.595 AC XY: 44151 AN XY: 74264

Gnomad4 AFR AF: 0.442

Gnomad4 AMR AF: 0.568

Gnomad4 ASJ AF: 0.609

Gnomad4 EAS AF: 0.485

Gnomad4 SAS AF: 0.460

Gnomad4 FIN AF: 0.753

Gnomad4 NFE AF: 0.691

Gnomad4 OTH AF: 0.598

Alfa AF: 0.656 Hom.: 69506

Bravo AF: 0.574

TwinsUK AF: 0.704 AC: 2610

ALSPAC AF: 0.696 AC: 2684

ESP6500AA AF: 0.443 AC: 1951

ESP6500EA AF: 0.683 AC: 5871

ExAC AF: 0.606 AC: 73516

Asia WGS AF: 0.450 AC: 1569 AN: 3478

EpiCase AF: 0.673

EpiControl AF: 0.665

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.0000057	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	7.6e-7	P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;B
Vest4		0.24
MPC		0.21
ClinPred		0.030	T
GERP RS		5.7
Varity_R		0.54
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2275687; hg19: chr1-236717926; COSMIC: COSV63979833; COSMIC: COSV63979833;