rs8685

Variant names:

• chr8-33500752-G-A
• rs8685
• NM_032509.4:c.*2123G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032509.4(MAK16):​c.*2123G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 410,674 control chromosomes in the GnomAD database, including 62,304 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.53 (21822 hom., cov: 32)
  • Exomes 𝑓: 0.56 (40482 hom.)
• Consequence: MAK16 NM_032509.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.34
• Publications: 17 publications found

Genes affected

MAK16 (HGNC:13703): (MAK16 homolog) Enables RNA binding activity. Predicted to be involved in maturation of 5.8S rRNA and maturation of LSU-rRNA. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

TTI2 (HGNC:26262): (TELO2 interacting protein 2) This gene encodes a regulator of the DNA damage response. The protein is a component of the Triple T complex (TTT) which also includes telomere length regulation protein and TELO2 interacting protein 1. The TTT complex is involved in cellular resistance to DNA damage stresses and may act as a regulator of phosphoinositide-3-kinase-related protein kinase (PIKK) abundance. [provided by RefSeq, May 2013]

TTI2 Gene-Disease associations (from GenCC):

• severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032509.4. 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
	MAK16	NM_032509.4	MANE Select	c.*2123G>A		3_prime_UTR	Exon 10 of 10	NP_115898.2
	TTI2	NM_001102401.4	MANE Select	c.1260-262C>T		intron	N/A	NP_001095871.1	Q6NXR4
	TTI2	NM_001265581.2		c.1260-262C>T		intron	N/A	NP_001252510.1	Q6NXR4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAK16	ENST00000360128.11	TSL:1 MANE Select	c.*2123G>A		3_prime_UTR	Exon 10 of 10	ENSP00000353246.5	Q9BXY0
	TTI2	ENST00000431156.7	TSL:1 MANE Select	c.1260-262C>T		intron	N/A	ENSP00000411169.3	Q6NXR4
	TTI2	ENST00000613904.1	TSL:1	c.1260-262C>T		intron	N/A	ENSP00000478396.1	Q6NXR4

Frequencies

GnomAD3 genomes AF: 0.531 AC: 80594 AN: 151780 Hom.: 21819 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.527

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.522

GnomAD4 exome AF: 0.557 AC: 144257 AN: 258778 Hom.: 40482 Cov.: 3 AF XY: 0.549 AC XY: 75947 AN XY: 138238

African (AFR) AF: 0.461 AC: 3550 AN: 7704

American (AMR) AF: 0.456 AC: 4953 AN: 10864

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 3997 AN: 7554

East Asian (EAS) AF: 0.512 AC: 7465 AN: 14582

South Asian (SAS) AF: 0.447 AC: 15568 AN: 34818

European-Finnish (FIN) AF: 0.605 AC: 7670 AN: 12670

Middle Eastern (MID) AF: 0.570 AC: 596 AN: 1046

European-Non Finnish (NFE) AF: 0.594 AC: 92169 AN: 155042

Other (OTH) AF: 0.572 AC: 8289 AN: 14498

GnomAD4 genome AF: 0.531 AC: 80623 AN: 151896 Hom.: 21822 Cov.: 32 AF XY: 0.530 AC XY: 39305 AN XY: 74224

African (AFR) AF: 0.449 AC: 18614 AN: 41412

American (AMR) AF: 0.495 AC: 7556 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 1827 AN: 3464

East Asian (EAS) AF: 0.492 AC: 2538 AN: 5154

South Asian (SAS) AF: 0.437 AC: 2101 AN: 4810

European-Finnish (FIN) AF: 0.597 AC: 6296 AN: 10548

Middle Eastern (MID) AF: 0.551 AC: 161 AN: 292

European-Non Finnish (NFE) AF: 0.586 AC: 39830 AN: 67944

Other (OTH) AF: 0.524 AC: 1105 AN: 2110

Alfa AF: 0.561 Hom.: 24881

Bravo AF: 0.521

Asia WGS AF: 0.439 AC: 1527 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.16
DANN	Benign	0.46
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs8685; hg19: chr8-33358270;