3-9810179-G-A

Variant names:

• chr3-9810179-G-A
• rs1250170944
• ENST00000397256.5:c.331-2764G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001025930.5(TTLL3):​c.173G>A​(p.Arg58His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000304 in 1,317,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R58L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: TTLL3 NM_001025930.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 0 publications found

Genes affected

ARPC4-TTLL3 (HGNC:38830): (ARPC4-TTLL3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ARPC4 (actin related protein 2/3 complex, subunit 4) and TTLL3 (tubulin tyrosine ligase-like family, member 3) genes. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Nov 2010]

TTLL3 (HGNC:24483): (tubulin tyrosine ligase like 3) Enables protein-glycine ligase activity. Predicted to be involved in axoneme assembly and flagellated sperm motility. Predicted to be located in axoneme; microtubule cytoskeleton; and sperm flagellum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085896134).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025930.5. 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
	TTLL3	NM_001025930.5		c.173G>A	p.Arg58His	missense	Exon 1 of 13	NP_001021100.3	J3KQB2
	TTLL3	NM_001387448.1		c.-42+257G>A		intron	N/A	NP_001374377.1
	ARPC4-TTLL3	NM_001198793.1		c.331-2764G>A		intron	N/A	NP_001185722.1	A0A0A6YYG9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARPC4-TTLL3	ENST00000397256.5	TSL:5	c.331-2764G>A		intron	N/A	ENSP00000380427.1
	TTLL3	ENST00000427220.5	TSL:1	n.-483G>A		non_coding_transcript_exon	Exon 1 of 11	ENSP00000395912.1	F8WD18
	TTLL3	ENST00000427220.5	TSL:1	n.-483G>A		5_prime_UTR	Exon 1 of 11	ENSP00000395912.1	F8WD18

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000304 AC: 4 AN: 1317528 Hom.: 0 Cov.: 70 AF XY: 0.00000154 AC XY: 1 AN XY: 648666

African (AFR) AF: 0.00 AC: 0 AN: 26332

American (AMR) AF: 0.00 AC: 0 AN: 24060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22946

East Asian (EAS) AF: 0.00 AC: 0 AN: 28858

South Asian (SAS) AF: 0.00 AC: 0 AN: 72276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4486

European-Non Finnish (NFE) AF: 0.00000381 AC: 4 AN: 1051134

Other (OTH) AF: 0.00 AC: 0 AN: 54742

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.8
DANN	Uncertain	1.0
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.99	T
PhyloP100		-1.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.022
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.028	D
Vest4		0.083
MutPred		0.27		Loss of MoRF binding (P = 0.0069)
MVP		0.092
MPC		0.11
ClinPred		0.15	T
GERP RS		0.59
PromoterAI		-0.14	Neutral
gMVP		0.15

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: rs1250170944; hg19: chr3-9851863;