rs2306630

Positions:

• chr17-35855337-G-A

Variant summary

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

The NM_152781.4(HEATR9):​c.1439C>T​(p.Ser480Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,613,866 control chromosomes in the GnomAD database, including 18,191 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2229 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15962 hom.)
• Consequence: HEATR9 NM_152781.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0780

Genes affected

HEATR9 (HGNC:26548): (HEAT repeat containing 9) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

TAF15 (HGNC:11547): (TATA-box binding protein associated factor 15) This gene encodes a member of the TET family of RNA-binding proteins. The encoded protein plays a role in RNA polymerase II gene transcription as a component of a distinct subset of multi-subunit transcription initiation factor TFIID complexes. Translocations involving this gene play a role in acute leukemia and extraskeletal myxoid chondrosarcoma, and mutations in this gene may play a role in amyotrophic lateral sclerosis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

HEATR9 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011040837).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEATR9	NM_152781.4	c.1439C>T	p.Ser480Phe	missense_variant	15/15	ENST00000604834.6	NP_689994.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEATR9	ENST00000604834.6	c.1439C>T	p.Ser480Phe	missense_variant	15/15	1	NM_152781.4	ENSP00000473941.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24526 AN: 152048 Hom.: 2217 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.153

GnomAD3 exomes AF: 0.167 AC: 41920 AN: 251428 Hom.: 4107 AF XY: 0.160 AC XY: 21679 AN XY: 135900

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.337

Gnomad SAS exome AF: 0.118

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.140 AC: 204572 AN: 1461700 Hom.: 15962 Cov.: 32 AF XY: 0.139 AC XY: 100747 AN XY: 727164

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.235

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.344

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.161 AC: 24570 AN: 152166 Hom.: 2229 Cov.: 32 AF XY: 0.162 AC XY: 12070 AN XY: 74392

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.332

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.155

Alfa AF: 0.142 Hom.: 3673

Bravo AF: 0.170

TwinsUK AF: 0.137 AC: 507

ALSPAC AF: 0.140 AC: 540

ESP6500AA AF: 0.198 AC: 873

ESP6500EA AF: 0.129 AC: 1106

ExAC AF: 0.162 AC: 19658

Asia WGS AF: 0.194 AC: 676 AN: 3478

EpiCase AF: 0.134

EpiControl AF: 0.133

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.11
DANN	Benign	0.091
DEOGEN2	Benign	0.0028	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00059	N
LIST_S2	Benign	0.16	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.4	N;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.075
ClinPred		0.000014	T
GERP RS		3.0
Varity_R		0.036
gMVP		0.083

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2306630; hg19: chr17-34182341;