NM_001145440.3:c.899G>A

Variant names:

• chr7-72777481-C-T
• NM_001145440.3:c.899G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001145440.3(TYW1B):​c.899G>A​(p.Arg300Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TYW1B NM_001145440.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.752
• Publications: 0 publications found

Genes affected

TYW1B (HGNC:33908): (tRNA-yW synthesizing protein 1 homolog B) Wybutosine is a hypermodified guanosine found in phenylalanine tRNA. Wybutosine functions to stabilize codon-anticodon interactions during ribosome decoding and therefore supports the maintenance of the reading frame. In yeast, the homolog of this gene is essential for the synthesis of wybutosine. The human genome contains two closely related genes that putatively function in wybutosine synthesis. The open reading frame of this locus is disrupted in some individuals. Thus, this locus appears to be an evolving pseudogene, but may still be functional in some members of the population. [provided by RefSeq, Apr 2014]

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=0.11208239).
• BP6: Variant 7-72777481-C-T is Benign according to our data. Variant chr7-72777481-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2340518.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145440.3. 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
	TYW1B	NM_001145440.3	MANE Select	c.899G>A	p.Arg300Lys	missense	Exon 7 of 14	NP_001138912.2	Q6NUM6-1
	TYW1B	NM_001412179.1		c.899G>A	p.Arg300Lys	missense	Exon 7 of 12	NP_001399108.1
	TYW1B	NM_001412180.1		c.899G>A	p.Arg300Lys	missense	Exon 7 of 11	NP_001399109.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYW1B	ENST00000620995.5	TSL:1 MANE Select	c.899G>A	p.Arg300Lys	missense	Exon 7 of 14	ENSP00000482502.1	Q6NUM6-1
	TYW1B	ENST00000612372.4	TSL:1	c.413G>A	p.Arg138Lys	missense	Exon 5 of 12	ENSP00000480534.1	A0A087WWV6
	TYW1B	ENST00000902318.1		c.899G>A	p.Arg300Lys	missense	Exon 7 of 12	ENSP00000572377.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461820 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00194278), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.063
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.64
DANN	Benign	0.76
DEOGEN2	Benign	0.0025	T
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.00056	T
MetaRNN	Benign	0.11	T
PhyloP100		0.75
PrimateAI	Benign	0.47	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.34
GERP RS		1.7
Varity_R		0.041
gMVP		0.15
Mutation Taster		=100/0	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

hg19: chr7-72242492;