chr3-57489624-T-G

Position:

• chr3-57489624-T-G

Variant summary

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

The NM_001366028.2(DNAH12):​c.1399A>C​(p.Thr467Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 1,540,110 control chromosomes in the GnomAD database, including 353,121 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34243 hom., cov: 30)
  • Exomes 𝑓: 0.68 (318878 hom.)
• Consequence: DNAH12 NM_001366028.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.87

Genes affected

DNAH12 (HGNC:2943): (dynein axonemal heavy chain 12) Predicted to enable several functions, including ATP binding activity; dynein intermediate chain binding activity; and dynein light intermediate chain binding activity. Predicted to be involved in microtubule-based movement. Predicted to be located in cilium; cytoplasm; and microtubule. Predicted to be part of dynein complex. [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=6.864867E-7).
• BP6: Variant 3-57489624-T-G is Benign according to our data. Variant chr3-57489624-T-G is described in ClinVar as [Benign]. Clinvar id is 402642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH12	NM_001366028.2	c.1399A>C	p.Thr467Pro	missense_variant	12/74	ENST00000495027.6	NP_001352957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH12	ENST00000495027.6	c.1399A>C	p.Thr467Pro	missense_variant	12/74	5	NM_001366028.2	ENSP00000418137.2
DNAH12	ENST00000351747.6	c.1399A>C	p.Thr467Pro	missense_variant	12/59	5		ENSP00000295937.3
DNAH12	ENST00000389536.8	c.1399A>C	p.Thr467Pro	missense_variant	12/17	5		ENSP00000374187.4

Frequencies

GnomAD3 genomes AF: 0.670 AC: 101478 AN: 151496 Hom.: 34237 Cov.: 30

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.832

Gnomad AMR AF: 0.637

Gnomad ASJ AF: 0.790

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.677

GnomAD3 exomes AF: 0.672 AC: 97268 AN: 144648 Hom.: 33373 AF XY: 0.681 AC XY: 52316 AN XY: 76786

Gnomad AFR exome AF: 0.639

Gnomad AMR exome AF: 0.587

Gnomad ASJ exome AF: 0.794

Gnomad EAS exome AF: 0.465

Gnomad SAS exome AF: 0.764

Gnomad FIN exome AF: 0.727

Gnomad NFE exome AF: 0.679

Gnomad OTH exome AF: 0.673

GnomAD4 exome AF: 0.676 AC: 938852 AN: 1388496 Hom.: 318878 Cov.: 47 AF XY: 0.679 AC XY: 465001 AN XY: 684538

Gnomad4 AFR exome AF: 0.645

Gnomad4 AMR exome AF: 0.597

Gnomad4 ASJ exome AF: 0.795

Gnomad4 EAS exome AF: 0.519

Gnomad4 SAS exome AF: 0.759

Gnomad4 FIN exome AF: 0.721

Gnomad4 NFE exome AF: 0.673

Gnomad4 OTH exome AF: 0.679

GnomAD4 genome AF: 0.670 AC: 101531 AN: 151614 Hom.: 34243 Cov.: 30 AF XY: 0.673 AC XY: 49833 AN XY: 74090

Gnomad4 AFR AF: 0.645

Gnomad4 AMR AF: 0.636

Gnomad4 ASJ AF: 0.790

Gnomad4 EAS AF: 0.489

Gnomad4 SAS AF: 0.751

Gnomad4 FIN AF: 0.723

Gnomad4 NFE AF: 0.683

Gnomad4 OTH AF: 0.675

Alfa AF: 0.678 Hom.: 64536

Bravo AF: 0.658

TwinsUK AF: 0.688 AC: 2551

ALSPAC AF: 0.668 AC: 2573

ESP6500AA AF: 0.629 AC: 871

ESP6500EA AF: 0.686 AC: 2182

ExAC AF: 0.700 AC: 16371

Asia WGS AF: 0.657 AC: 2280 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.0072	T;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.071	T;T;T
MetaRNN	Benign	6.9e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	.;N;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	2.2	N;N;N
REVEL	Benign	0.077
Sift	Benign	0.46	T;T;T
Sift4G	Benign	1.0	.;.;T
Polyphen		0.0	.;B;.
Vest4		0.077
ClinPred		0.0060	T
GERP RS		5.4
Varity_R		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6806444; hg19: chr3-57475351; COSMIC: COSV61055961; COSMIC: COSV61055961;