3-57301848-C-T

Position:

• chr3-57301848-C-T

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.11281G>A​(p.Gly3761Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 1,551,332 control chromosomes in the GnomAD database, including 304,603 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 0.61 (28517 hom., cov: 31)
  • Exomes 𝑓: 0.62 (276086 hom.)
• Consequence: DNAH12 NM_001366028.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.479

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=4.1477865E-6).
• BP6: Variant 3-57301848-C-T is Benign according to our data. Variant chr3-57301848-C-T is described in ClinVar as [Benign]. Clinvar id is 402630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH12	NM_001366028.2	c.11281G>A	p.Gly3761Ser	missense_variant	70/74	ENST00000495027.6	NP_001352957.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH12	ENST00000495027.6	c.11281G>A	p.Gly3761Ser	missense_variant	70/74	5	NM_001366028.2	ENSP00000418137.2
DNAH12	ENST00000351747.6	c.8677G>A	p.Gly2893Ser	missense_variant	55/59	5		ENSP00000295937.3
DNAH12	ENST00000466540.2	c.1618G>A	p.Gly540Ser	missense_variant	11/15	5		ENSP00000420359.2
DNAH12	ENST00000494758.5	n.96-4864G>A		intron_variant		2		ENSP00000420717.1

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91889 AN: 151810 Hom.: 28492 Cov.: 31

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.718

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.924

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.599

GnomAD3 exomes AF: 0.660 AC: 103557 AN: 156914 Hom.: 35174 AF XY: 0.655 AC XY: 54385 AN XY: 83086

Gnomad AFR exome AF: 0.486

Gnomad AMR exome AF: 0.766

Gnomad ASJ exome AF: 0.566

Gnomad EAS exome AF: 0.939

Gnomad SAS exome AF: 0.619

Gnomad FIN exome AF: 0.694

Gnomad NFE exome AF: 0.611

Gnomad OTH exome AF: 0.625

GnomAD4 exome AF: 0.624 AC: 873762 AN: 1399404 Hom.: 276086 Cov.: 63 AF XY: 0.624 AC XY: 430442 AN XY: 690200

Gnomad4 AFR exome AF: 0.480

Gnomad4 AMR exome AF: 0.754

Gnomad4 ASJ exome AF: 0.563

Gnomad4 EAS exome AF: 0.913

Gnomad4 SAS exome AF: 0.622

Gnomad4 FIN exome AF: 0.692

Gnomad4 NFE exome AF: 0.614

Gnomad4 OTH exome AF: 0.625

GnomAD4 genome AF: 0.605 AC: 91965 AN: 151928 Hom.: 28517 Cov.: 31 AF XY: 0.611 AC XY: 45349 AN XY: 74256

Gnomad4 AFR AF: 0.490

Gnomad4 AMR AF: 0.718

Gnomad4 ASJ AF: 0.557

Gnomad4 EAS AF: 0.924

Gnomad4 SAS AF: 0.644

Gnomad4 FIN AF: 0.695

Gnomad4 NFE AF: 0.612

Gnomad4 OTH AF: 0.604

Alfa AF: 0.616 Hom.: 55229

Bravo AF: 0.603

TwinsUK AF: 0.618 AC: 2293

ALSPAC AF: 0.614 AC: 2367

ESP6500AA AF: 0.499 AC: 691

ESP6500EA AF: 0.611 AC: 1943

ExAC AF: 0.602 AC: 14725

Asia WGS AF: 0.765 AC: 2657 AN: 3478

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	0.086
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.056
DANN	Benign	0.18
DEOGEN2	Benign	0.0010	T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	0.0000041	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.060	.;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.31	.;N
REVEL	Benign	0.15
Sift	Benign	1.0	.;T
Polyphen		0.12	.;B
Vest4		0.050
ClinPred		0.0013	T
GERP RS		2.3
Varity_R		0.060

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: rs4060726; hg19: chr3-57335876; COSMIC: COSV61054598; COSMIC: COSV61054598;