rs6661946

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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=0.005476624).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEATR1	NM_018072.6	c.4676G>A	p.Ser1559Asn	missense_variant	Exon 34 of 45	ENST00000366582.8	NP_060542.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEATR1	ENST00000366582.8	c.4676G>A	p.Ser1559Asn	missense_variant	Exon 34 of 45	5	NM_018072.6	ENSP00000355541.3
HEATR1	ENST00000366581.6	c.4433G>A	p.Ser1478Asn	missense_variant	Exon 33 of 44	5		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

GnomAD3 exomes AF: 0.0765 AC: 19183 AN: 250746 Hom.: 1511 AF XY: 0.0687 AC XY: 9313 AN XY: 135516

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 SAS exome AF: 0.0675

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

Gnomad4 AFR exome AF: 0.329

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.0714

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.0666

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.0327

Gnomad4 OTH exome AF: 0.0697

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

Gnomad4 AFR AF: 0.315

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.0752

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.0726

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.0332

Gnomad4 OTH AF: 0.129

Alfa AF: 0.0582 Hom.: 1269

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 v4.3

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;T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.4	N;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.099
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.055
MPC		0.087
ClinPred		0.0028	T
GERP RS		4.6
Varity_R		0.018
gMVP		0.080

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: rs6661946; hg19: chr1-236723108; COSMIC: COSV63981245;