3-57296414-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001366028.2(DNAH12):​c.11554G>T​(p.Asp3852Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D3852N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAH12 NM_001366028.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20906392).

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>T	p.Asp3852Tyr	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>T	p.Asp3852Tyr	missense	Exon 72 of 74	ENSP00000418137.2	E9PG32
	DNAH12	ENST00000351747.6	TSL:5	c.8950G>T	p.Asp2984Tyr	missense	Exon 57 of 59	ENSP00000295937.3	Q6ZR08-1
	DNAH12	ENST00000466540.2	TSL:5	c.1891G>T	p.Asp631Tyr	missense	Exon 13 of 15	ENSP00000420359.2	H7C5N3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.68
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.8
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.10
Sift	Benign	0.067	T
Polyphen		0.99	D
Vest4		0.24
MutPred		0.47		Gain of catalytic residue at D2984 (P = 0.0361)
MVP		0.33
ClinPred		0.83	D
GERP RS		2.1
Varity_R		0.20
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs905631718; hg19: chr3-57330442;