11-113323446-A-C

Position:

• chr11-113323446-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017868.4(TTC12):​c.217A>C​(p.Met73Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 1,573,520 control chromosomes in the GnomAD database, including 184,062 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.40 (13571 hom., cov: 32)
  • Exomes 𝑓: 0.49 (170491 hom.)
• Consequence: TTC12 NM_017868.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.10

Genes affected

TTC12 (HGNC:23700): (tetratricopeptide repeat domain 12) Involved in axonemal dynein complex assembly and sperm axoneme assembly. Located in centrosome and cytoplasm. Implicated in primary ciliary dyskinesia 45. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7309189E-4).
• BP6: Variant 11-113323446-A-C is Benign according to our data. Variant chr11-113323446-A-C is described in ClinVar as [Benign]. Clinvar id is 1258984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC12	NM_017868.4	c.217A>C	p.Met73Leu	missense_variant	3/22	ENST00000529221.6	NP_060338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC12	ENST00000529221.6	c.217A>C	p.Met73Leu	missense_variant	3/22	2	NM_017868.4	ENSP00000433757	A2

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60535 AN: 151910 Hom.: 13575 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.420

GnomAD3 exomes AF: 0.468 AC: 104013 AN: 222224 Hom.: 25067 AF XY: 0.475 AC XY: 57559 AN XY: 121080

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.518

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.429

Gnomad SAS exome AF: 0.499

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.500

Gnomad OTH exome AF: 0.461

GnomAD4 exome AF: 0.486 AC: 690734 AN: 1421492 Hom.: 170491 Cov.: 32 AF XY: 0.486 AC XY: 343907 AN XY: 707032

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.496

Gnomad4 ASJ exome AF: 0.518

Gnomad4 EAS exome AF: 0.395

Gnomad4 SAS exome AF: 0.492

Gnomad4 FIN exome AF: 0.445

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.466

GnomAD4 genome AF: 0.398 AC: 60531 AN: 152028 Hom.: 13571 Cov.: 32 AF XY: 0.398 AC XY: 29546 AN XY: 74308

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.442

Gnomad4 ASJ AF: 0.524

Gnomad4 EAS AF: 0.416

Gnomad4 SAS AF: 0.486

Gnomad4 FIN AF: 0.445

Gnomad4 NFE AF: 0.498

Gnomad4 OTH AF: 0.420

Alfa AF: 0.481 Hom.: 41200

Bravo AF: 0.389

TwinsUK AF: 0.501 AC: 1859

ALSPAC AF: 0.495 AC: 1906

ESP6500AA AF: 0.194 AC: 852

ESP6500EA AF: 0.505 AC: 4339

ExAC AF: 0.461 AC: 56014

Asia WGS AF: 0.443 AC: 1538 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ciliary dyskinesia, primary, 45 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.0010
DANN	Benign	0.38
DEOGEN2	Benign	0.0082	T;T;T;.;.;.;T;.;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.47	T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.00017	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N;.;.;.;.;.;.;.;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.27	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.011
Sift	Benign	0.96	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.78	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.;.;.;.;.
Vest4		0.017
MutPred		0.27		Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);.;Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);Loss of catalytic residue at M73 (P = 0.0084);
MPC		0.067
ClinPred		0.0067	T
GERP RS		-8.6
Varity_R		0.052
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs723077; hg19: chr11-113194168; COSMIC: COSV59097115; COSMIC: COSV59097115;