NM_182922.4:c.49A>G

Variant names:

• chr16-50066180-A-G
• rs940474435
• NM_182922.4:c.49A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182922.4(HEATR3):​c.49A>G​(p.Thr17Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,593,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: HEATR3 NM_182922.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32
• Publications: 1 publications found

Genes affected

HEATR3 (HGNC:26087): (HEAT repeat containing 3) The protein encoded by this gene plays a role in ribosomal protein transport and in the assembly of the 5S ribonucleoprotein particle (5S RNP). The encoded protein also may be involved in NOD2-mediated NF-kappaB signaling. [provided by RefSeq, Jul 2016]

HEATR3-AS1 (HGNC:55406): (HEATR3 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06726518).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182922.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEATR3	NM_182922.4	MANE Select	c.49A>G	p.Thr17Ala	missense	Exon 1 of 15	NP_891552.1	Q7Z4Q2-1
	HEATR3	NM_001329729.2		c.-644A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001316658.1
	HEATR3	NM_001329730.2		c.-618A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001316659.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEATR3	ENST00000299192.8	TSL:1 MANE Select	c.49A>G	p.Thr17Ala	missense	Exon 1 of 15	ENSP00000299192.7	Q7Z4Q2-1
	HEATR3	ENST00000887924.1		c.49A>G	p.Thr17Ala	missense	Exon 1 of 15	ENSP00000557983.1
	HEATR3	ENST00000887923.1		c.49A>G	p.Thr17Ala	missense	Exon 1 of 14	ENSP00000557982.1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 151054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000189 AC: 4 AN: 212058 AF XY: 0.0000260

Gnomad AFR exome AF: 0.0000840

Gnomad AMR exome AF: 0.0000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000214

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1441954 Hom.: 0 Cov.: 30 AF XY: 0.0000154 AC XY: 11 AN XY: 715672

African (AFR) AF: 0.0000307 AC: 1 AN: 32560

American (AMR) AF: 0.0000239 AC: 1 AN: 41880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25468

East Asian (EAS) AF: 0.00 AC: 0 AN: 38744

South Asian (SAS) AF: 0.00 AC: 0 AN: 83232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.0000127 AC: 14 AN: 1103892

Other (OTH) AF: 0.00 AC: 0 AN: 59666

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 151054 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73738

African (AFR) AF: 0.0000488 AC: 2 AN: 41006

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67738

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.0000868 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.0071	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.096
Sift	Benign	0.12	T
Sift4G	Benign	0.20	T
Polyphen		0.049	B
Vest4		0.14
MutPred		0.13		Loss of phosphorylation at T17 (P = 0.0096)
MVP		0.43
MPC		0.23
ClinPred		0.078	T
GERP RS		1.7
PromoterAI		-0.039	Neutral
Varity_R		0.14
gMVP		0.34
Mutation Taster		=90/10	polymorphism

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: rs940474435; hg19: chr16-50100091;