NM_001366028.2:c.4714G>A

Variant names:

• chr3-57433770-C-T
• rs6773904
• NM_001366028.2:c.4714G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001366028.2(DNAH12):​c.4714G>A​(p.Asp1572Asn) variant causes a missense change. The variant allele was found at a frequency of 0.486 in 1,550,106 control chromosomes in the GnomAD database, including 187,650 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15034 hom., cov: 32)
  • Exomes 𝑓: 0.49 (172616 hom.)
• Consequence: DNAH12 NM_001366028.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.07
• Publications: 17 publications found

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]

DNAH12 Gene-Disease associations (from GenCC):

• spermatogenic failure

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• oligoasthenoteratozoospermia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.866323E-4).
• BP6: Variant 3-57433770-C-T is Benign according to our data. Variant chr3-57433770-C-T is described in ClinVar as Benign. ClinVar VariationId is 402636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366028.2. 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
	DNAH12	NM_001366028.2	MANE Select	c.4714G>A	p.Asp1572Asn	missense	Exon 31 of 74	NP_001352957.1	E9PG32

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH12	ENST00000495027.6	TSL:5 MANE Select	c.4714G>A	p.Asp1572Asn	missense	Exon 31 of 74	ENSP00000418137.2	E9PG32
	DNAH12	ENST00000351747.6	TSL:5	c.4645G>A	p.Asp1549Asn	missense	Exon 31 of 59	ENSP00000295937.3	Q6ZR08-1

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63735 AN: 151884 Hom.: 15034 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.455

GnomAD2 exomes AF: 0.494 AC: 75600 AN: 152926 AF XY: 0.503

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.470

Gnomad ASJ exome AF: 0.585

Gnomad EAS exome AF: 0.412

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.501

Gnomad OTH exome AF: 0.504

GnomAD4 exome AF: 0.493 AC: 688985 AN: 1398106 Hom.: 172616 Cov.: 46 AF XY: 0.497 AC XY: 342378 AN XY: 689498

African (AFR) AF: 0.177 AC: 5587 AN: 31564

American (AMR) AF: 0.473 AC: 16806 AN: 35512

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 14691 AN: 25142

East Asian (EAS) AF: 0.442 AC: 15775 AN: 35702

South Asian (SAS) AF: 0.563 AC: 44438 AN: 78886

European-Finnish (FIN) AF: 0.569 AC: 27944 AN: 49108

Middle Eastern (MID) AF: 0.566 AC: 3223 AN: 5690

European-Non Finnish (NFE) AF: 0.493 AC: 531948 AN: 1078540

Other (OTH) AF: 0.493 AC: 28573 AN: 57962

GnomAD4 genome AF: 0.419 AC: 63737 AN: 152000 Hom.: 15034 Cov.: 32 AF XY: 0.428 AC XY: 31786 AN XY: 74272

African (AFR) AF: 0.188 AC: 7819 AN: 41488

American (AMR) AF: 0.481 AC: 7350 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 2000 AN: 3462

East Asian (EAS) AF: 0.421 AC: 2175 AN: 5170

South Asian (SAS) AF: 0.570 AC: 2743 AN: 4810

European-Finnish (FIN) AF: 0.580 AC: 6117 AN: 10546

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.498 AC: 33863 AN: 67944

Other (OTH) AF: 0.456 AC: 962 AN: 2110

Alfa AF: 0.477 Hom.: 36822

Bravo AF: 0.397

TwinsUK AF: 0.499 AC: 1850

ALSPAC AF: 0.486 AC: 1874

ESP6500AA AF: 0.184 AC: 254

ESP6500EA AF: 0.497 AC: 1582

ExAC AF: 0.480 AC: 10186

Asia WGS AF: 0.512 AC: 1782 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.022	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.00079	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L
PhyloP100		6.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.19
Sift	Benign	0.37	T
Polyphen		0.99	D
Vest4		0.15
ClinPred		0.051	T
GERP RS		4.9
Varity_R		0.10
Mutation Taster		=88/12	polymorphism (auto)

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: rs6773904; hg19: chr3-57419497; COSMIC: COSV61056362;