8-33498368-G-T

Variant names:

• chr8-33498368-G-T
• rs2676419
• NM_032509.4:c.706-64G>T

Variant summary

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

The NM_032509.4(MAK16):​c.706-64G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 1,442,360 control chromosomes in the GnomAD database, including 285,331 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 0.64 (31002 hom., cov: 31)
  • Exomes 𝑓: 0.62 (254329 hom.)
• Consequence: MAK16 NM_032509.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.434
• Publications: 8 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAK16	NM_032509.4	c.706-64G>T		intron_variant	Intron 9 of 9	ENST00000360128.11	NP_115898.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAK16	ENST00000360128.11	c.706-64G>T		intron_variant	Intron 9 of 9	1	NM_032509.4	ENSP00000353246.5
MAK16	ENST00000518389.1	n.*246-64G>T		intron_variant	Intron 8 of 8	5		ENSP00000430403.1
TTI2	ENST00000519356.1	n.628+1960C>A		intron_variant	Intron 5 of 5	3
TTI2	ENST00000613904.1	c.*805C>A		downstream_gene_variant		1		ENSP00000478396.1

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96458 AN: 151606 Hom.: 30985 Cov.: 31

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.571

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.651

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.618

GnomAD4 exome AF: 0.625 AC: 806550 AN: 1290640 Hom.: 254329 AF XY: 0.622 AC XY: 401574 AN XY: 646002

African (AFR) AF: 0.684 AC: 20278 AN: 29654

American (AMR) AF: 0.445 AC: 16989 AN: 38172

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 13521 AN: 22932

East Asian (EAS) AF: 0.566 AC: 21617 AN: 38226

South Asian (SAS) AF: 0.500 AC: 38445 AN: 76920

European-Finnish (FIN) AF: 0.649 AC: 33199 AN: 51138

Middle Eastern (MID) AF: 0.614 AC: 3058 AN: 4984

European-Non Finnish (NFE) AF: 0.642 AC: 625132 AN: 974210

Other (OTH) AF: 0.631 AC: 34311 AN: 54404

GnomAD4 genome AF: 0.636 AC: 96515 AN: 151720 Hom.: 31002 Cov.: 31 AF XY: 0.634 AC XY: 47021 AN XY: 74144

African (AFR) AF: 0.681 AC: 28157 AN: 41332

American (AMR) AF: 0.550 AC: 8383 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 2048 AN: 3468

East Asian (EAS) AF: 0.571 AC: 2945 AN: 5156

South Asian (SAS) AF: 0.497 AC: 2392 AN: 4812

European-Finnish (FIN) AF: 0.651 AC: 6831 AN: 10490

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43657 AN: 67914

Other (OTH) AF: 0.621 AC: 1308 AN: 2106

Alfa AF: 0.585 Hom.: 3185

Bravo AF: 0.631

Asia WGS AF: 0.524 AC: 1824 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.43
DANN	Benign	0.53
PhyloP100		-0.43
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: rs2676419; hg19: chr8-33355886;