chr1-236559808-C-T

Variant names:

• chr1-236559808-C-T
• rs6661946
• NM_018072.6:c.4676G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018072.6(HEATR1):​c.4676G>A​(p.Ser1559Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0559 in 1,612,834 control chromosomes in the GnomAD database, including 6,168 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (2306 hom., cov: 32)
  • Exomes 𝑓: 0.049 (3862 hom.)
• Consequence: HEATR1 NM_018072.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.73
• Publications: 23 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005476624).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018072.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEATR1	NM_018072.6	MANE Select	c.4676G>A	p.Ser1559Asn	missense	Exon 34 of 45	NP_060542.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEATR1	ENST00000366582.8	TSL:5 MANE Select	c.4676G>A	p.Ser1559Asn	missense	Exon 34 of 45	ENSP00000355541.3
	HEATR1	ENST00000366581.6	TSL:5	c.4433G>A	p.Ser1478Asn	missense	Exon 33 of 44	ENSP00000355540.2

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18902 AN: 151956 Hom.: 2298 Cov.: 32

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0752

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.0736

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0332

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.0765 AC: 19183 AN: 250746 AF XY: 0.0687

Gnomad AFR exome AF: 0.321

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.0711

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0336

Gnomad OTH exome AF: 0.0680

GnomAD4 exome AF: 0.0488 AC: 71270 AN: 1460760 Hom.: 3862 Cov.: 31 AF XY: 0.0481 AC XY: 34926 AN XY: 726594

African (AFR) AF: 0.329 AC: 11003 AN: 33436

American (AMR) AF: 0.123 AC: 5493 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.0714 AC: 1865 AN: 26106

East Asian (EAS) AF: 0.133 AC: 5288 AN: 39658

South Asian (SAS) AF: 0.0666 AC: 5735 AN: 86100

European-Finnish (FIN) AF: 0.0125 AC: 670 AN: 53412

Middle Eastern (MID) AF: 0.123 AC: 709 AN: 5760

European-Non Finnish (NFE) AF: 0.0327 AC: 36302 AN: 1111374

Other (OTH) AF: 0.0697 AC: 4205 AN: 60320

GnomAD4 genome AF: 0.124 AC: 18930 AN: 152074 Hom.: 2306 Cov.: 32 AF XY: 0.122 AC XY: 9076 AN XY: 74348

African (AFR) AF: 0.315 AC: 13049 AN: 41388

American (AMR) AF: 0.116 AC: 1766 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0752 AC: 261 AN: 3470

East Asian (EAS) AF: 0.142 AC: 733 AN: 5180

South Asian (SAS) AF: 0.0726 AC: 350 AN: 4822

European-Finnish (FIN) AF: 0.0124 AC: 131 AN: 10602

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.0332 AC: 2255 AN: 68014

Other (OTH) AF: 0.129 AC: 272 AN: 2108

Alfa AF: 0.0688 Hom.: 3677

Bravo AF: 0.142

TwinsUK AF: 0.0307 AC: 114

ALSPAC AF: 0.0358 AC: 138

ESP6500AA AF: 0.317 AC: 1397

ESP6500EA AF: 0.0394 AC: 339

ExAC AF: 0.0795 AC: 9657

Asia WGS AF: 0.148 AC: 513 AN: 3478

EpiCase AF: 0.0384

EpiControl AF: 0.0411

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.4
DANN	Benign	0.14
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.030	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.4	N
PhyloP100		3.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.099
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.055
MPC		0.087
ClinPred		0.0028	T
GERP RS		4.6
Varity_R		0.018
gMVP		0.080
Mutation Taster		=99/1	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: rs6661946; hg19: chr1-236723108; COSMIC: COSV63981245;