3-9810110-A-G

Variant names:

• chr3-9810110-A-G
• rs1244896988
• ENST00000397256.5:c.331-2833A>G

Variant summary

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

The NM_001025930.5(TTLL3):​c.104A>G​(p.Asn35Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,459,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. N35T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TTLL3 NM_001025930.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.317
• 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: 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=0.04026833).

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.104A>G	p.Asn35Ser	missense	Exon 1 of 13	NP_001021100.3	J3KQB2
	TTLL3	NM_001387448.1		c.-42+188A>G		intron	N/A	NP_001374377.1
	ARPC4-TTLL3	NM_001198793.1		c.331-2833A>G		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.331-2833A>G		intron	N/A	ENSP00000380427.1
	TTLL3	ENST00000427220.5	TSL:1	n.-552A>G		non_coding_transcript_exon	Exon 1 of 11	ENSP00000395912.1	F8WD18
	TTLL3	ENST00000427220.5	TSL:1	n.-552A>G		5_prime_UTR	Exon 1 of 11	ENSP00000395912.1	F8WD18

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149464 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000298

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000107 AC: 14 AN: 1310454 Hom.: 0 Cov.: 71 AF XY: 0.0000124 AC XY: 8 AN XY: 645004

African (AFR) AF: 0.00 AC: 0 AN: 26370

American (AMR) AF: 0.00 AC: 0 AN: 23580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22866

East Asian (EAS) AF: 0.00 AC: 0 AN: 28436

South Asian (SAS) AF: 0.00 AC: 0 AN: 71364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4024

European-Non Finnish (NFE) AF: 0.0000134 AC: 14 AN: 1046882

Other (OTH) AF: 0.00 AC: 0 AN: 54414

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149464 Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1 AN XY: 72944

African (AFR) AF: 0.00 AC: 0 AN: 40514

American (AMR) AF: 0.00 AC: 0 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.00 AC: 0 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000298 AC: 2 AN: 67002

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.6
DANN	Benign	0.32
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.91	T
PhyloP100		-0.32
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.011
Sift	Benign	1.0	T
Sift4G	Benign	0.99	T
Vest4		0.015
MutPred		0.24		Loss of helix (P = 0.0237)
MVP		0.23
MPC		0.070
ClinPred		0.082	T
GERP RS		-1.5
PromoterAI		0.0088	Neutral
gMVP		0.019

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: rs1244896988; hg19: chr3-9851794;