rs2306630

Variant names:

• chr17-35855337-G-A
• rs2306630
• NM_152781.4:c.1439C>T

Variant summary

Our verdict is Benign. The variant received -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. 12/18 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 0.16 (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
• Publications: 31 publications found

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]

TAF15 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
HEATR9	NM_152781.4	c.1439C>T	p.Ser480Phe	missense_variant	Exon 15 of 15	ENST00000604834.6	NP_689994.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEATR9	ENST00000604834.6	c.1439C>T	p.Ser480Phe	missense_variant	Exon 15 of 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

GnomAD2 exomes AF: 0.167 AC: 41920 AN: 251428 AF XY: 0.160

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 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

African (AFR) AF: 0.200 AC: 6687 AN: 33476

American (AMR) AF: 0.235 AC: 10497 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4388 AN: 26136

East Asian (EAS) AF: 0.344 AC: 13643 AN: 39700

South Asian (SAS) AF: 0.121 AC: 10474 AN: 86254

European-Finnish (FIN) AF: 0.141 AC: 7541 AN: 53420

Middle Eastern (MID) AF: 0.158 AC: 913 AN: 5766

European-Non Finnish (NFE) AF: 0.127 AC: 141725 AN: 1111842

Other (OTH) AF: 0.144 AC: 8704 AN: 60390

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

African (AFR) AF: 0.200 AC: 8308 AN: 41516

American (AMR) AF: 0.181 AC: 2771 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 554 AN: 3472

East Asian (EAS) AF: 0.332 AC: 1713 AN: 5162

South Asian (SAS) AF: 0.124 AC: 597 AN: 4812

European-Finnish (FIN) AF: 0.147 AC: 1560 AN: 10604

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

European-Non Finnish (NFE) AF: 0.126 AC: 8539 AN: 67990

Other (OTH) AF: 0.155 AC: 327 AN: 2114

Alfa AF: 0.146 Hom.: 5591

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;.
PhyloP100		0.078
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

Other links and lift over

dbSNP: rs2306630; hg19: chr17-34182341;