chr3-57508411-A-C

Variant names:

• chr3-57508411-A-C
• rs6445902
• NM_001366028.2:c.672T>G

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.672T>G​(p.Asp224Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,605,692 control chromosomes in the GnomAD database, including 33,301 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6410 hom., cov: 32)
  • Exomes 𝑓: 0.18 (26891 hom.)
• Consequence: DNAH12 NM_001366028.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.396
• Publications: 20 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=3.632307E-4).
• BP6: Variant 3-57508411-A-C is Benign according to our data. Variant chr3-57508411-A-C is described in ClinVar as Benign. ClinVar VariationId is 402643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 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.672T>G	p.Asp224Glu	missense	Exon 7 of 74	NP_001352957.1	E9PG32
	DNAH12	NM_198564.4		c.672T>G	p.Asp224Glu	missense	Exon 7 of 12	NP_940966.2	Q6ZR08-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH12	ENST00000495027.6	TSL:5 MANE Select	c.672T>G	p.Asp224Glu	missense	Exon 7 of 74	ENSP00000418137.2	E9PG32
	DNAH12	ENST00000351747.6	TSL:5	c.672T>G	p.Asp224Glu	missense	Exon 7 of 59	ENSP00000295937.3	Q6ZR08-1
	DNAH12	ENST00000389536.8	TSL:5	c.672T>G	p.Asp224Glu	missense	Exon 7 of 17	ENSP00000374187.4

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38740 AN: 151934 Hom.: 6393 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.0677

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.222

GnomAD2 exomes AF: 0.179 AC: 43599 AN: 243238 AF XY: 0.176

Gnomad AFR exome AF: 0.473

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.0573

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.184 AC: 267524 AN: 1453640 Hom.: 26891 Cov.: 32 AF XY: 0.183 AC XY: 132306 AN XY: 722886

African (AFR) AF: 0.480 AC: 15788 AN: 32864

American (AMR) AF: 0.120 AC: 5123 AN: 42626

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 5258 AN: 25974

East Asian (EAS) AF: 0.0761 AC: 3006 AN: 39504

South Asian (SAS) AF: 0.186 AC: 15670 AN: 84168

European-Finnish (FIN) AF: 0.154 AC: 8192 AN: 53212

Middle Eastern (MID) AF: 0.176 AC: 1007 AN: 5728

European-Non Finnish (NFE) AF: 0.182 AC: 202152 AN: 1109454

Other (OTH) AF: 0.188 AC: 11328 AN: 60110

GnomAD4 genome AF: 0.255 AC: 38792 AN: 152052 Hom.: 6410 Cov.: 32 AF XY: 0.250 AC XY: 18554 AN XY: 74352

African (AFR) AF: 0.471 AC: 19530 AN: 41422

American (AMR) AF: 0.157 AC: 2398 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 705 AN: 3468

East Asian (EAS) AF: 0.0676 AC: 350 AN: 5176

South Asian (SAS) AF: 0.174 AC: 839 AN: 4814

European-Finnish (FIN) AF: 0.146 AC: 1544 AN: 10590

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12709 AN: 67992

Other (OTH) AF: 0.220 AC: 465 AN: 2112

Alfa AF: 0.205 Hom.: 14571

Bravo AF: 0.266

TwinsUK AF: 0.193 AC: 717

ALSPAC AF: 0.182 AC: 700

ESP6500AA AF: 0.470 AC: 2073

ESP6500EA AF: 0.190 AC: 1636

ExAC AF: 0.186 AC: 22618

EpiCase AF: 0.176

EpiControl AF: 0.176

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	0.12
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.4
DANN	Benign	0.91
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.00036	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.40
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.022
Sift	Benign	0.39	T
Sift4G	Benign	0.21	T
Polyphen		0.0090	B
Vest4		0.026
MutPred		0.23		Gain of glycosylation at T221 (P = 0.0582)
MPC		0.077
ClinPred		0.0030	T
GERP RS		-0.56
Varity_R		0.034
gMVP		0.10
Mutation Taster		=96/4	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: rs6445902; hg19: chr3-57494138; COSMIC: COSV60857772; COSMIC: COSV60857772;