3-57296414-C-T

Variant names:

• chr3-57296414-C-T
• rs905631718
• NM_001366028.2:c.11554G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001366028.2(DNAH12):​c.11554G>A​(p.Asp3852Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,550,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: DNAH12 NM_001366028.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76
• Publications: 0 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

ENSG00000286952 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09279731).

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.11554G>A	p.Asp3852Asn	missense	Exon 72 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.11554G>A	p.Asp3852Asn	missense	Exon 72 of 74	ENSP00000418137.2	E9PG32
	DNAH12	ENST00000351747.6	TSL:5	c.8950G>A	p.Asp2984Asn	missense	Exon 57 of 59	ENSP00000295937.3	Q6ZR08-1
	DNAH12	ENST00000466540.2	TSL:5	c.1891G>A	p.Asp631Asn	missense	Exon 13 of 15	ENSP00000420359.2	H7C5N3

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000128 AC: 2 AN: 156256 AF XY: 0.0000242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000572 AC: 8 AN: 1398664 Hom.: 0 Cov.: 30 AF XY: 0.0000101 AC XY: 7 AN XY: 689798

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35712

South Asian (SAS) AF: 0.00 AC: 0 AN: 79118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000556 AC: 6 AN: 1078454

Other (OTH) AF: 0.0000345 AC: 2 AN: 57978

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151984 Hom.: 0 Cov.: 32 AF XY: 0.0000809 AC XY: 6 AN XY: 74204

African (AFR) AF: 0.00 AC: 0 AN: 41364

American (AMR) AF: 0.000590 AC: 9 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.8
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.081
Sift	Benign	0.25	T
Polyphen		0.27	B
Vest4		0.10
MutPred		0.42		Gain of glycosylation at T2985 (P = 0.0537)
MVP		0.28
ClinPred		0.096	T
GERP RS		2.1
Varity_R		0.085
Mutation Taster		=88/12	polymorphism

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: rs905631718; hg19: chr3-57330442;