rs2121743

Variant names:

• chr3-57446258-G-A
• rs2121743
• NM_001366028.2:c.3952C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-57446258-G-A
• chr3-57446258-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001366028.2(DNAH12):​c.3952C>T​(p.Leu1318Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 1,550,246 control chromosomes in the GnomAD database, including 212,370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (17154 hom., cov: 32)
  • Exomes 𝑓: 0.52 (195216 hom.)
• Consequence: DNAH12 NM_001366028.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.16
• Publications: 14 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 3-57446258-G-A is Benign according to our data. Variant chr3-57446258-G-A is described in ClinVar as Benign. ClinVar VariationId is 402638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.577 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.3952C>T	p.Leu1318Leu	synonymous	Exon 27 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.3952C>T	p.Leu1318Leu	synonymous	Exon 27 of 74	ENSP00000418137.2	E9PG32
	DNAH12	ENST00000351747.6	TSL:5	c.3883C>T	p.Leu1295Leu	synonymous	Exon 27 of 59	ENSP00000295937.3	Q6ZR08-1

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68385 AN: 151868 Hom.: 17155 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.635

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.535

Gnomad OTH AF: 0.497

GnomAD2 exomes AF: 0.525 AC: 82766 AN: 157752 AF XY: 0.534

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.640

Gnomad EAS exome AF: 0.413

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.537

Gnomad OTH exome AF: 0.540

GnomAD4 exome AF: 0.524 AC: 733151 AN: 1398260 Hom.: 195216 Cov.: 39 AF XY: 0.528 AC XY: 364059 AN XY: 689638

African (AFR) AF: 0.202 AC: 6365 AN: 31534

American (AMR) AF: 0.500 AC: 17819 AN: 35648

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 16101 AN: 25168

East Asian (EAS) AF: 0.443 AC: 15808 AN: 35704

South Asian (SAS) AF: 0.589 AC: 46563 AN: 79018

European-Finnish (FIN) AF: 0.597 AC: 29517 AN: 49436

Middle Eastern (MID) AF: 0.607 AC: 3459 AN: 5694

European-Non Finnish (NFE) AF: 0.526 AC: 567100 AN: 1077998

Other (OTH) AF: 0.524 AC: 30419 AN: 58060

GnomAD4 genome AF: 0.450 AC: 68390 AN: 151986 Hom.: 17154 Cov.: 32 AF XY: 0.458 AC XY: 33999 AN XY: 74308

African (AFR) AF: 0.211 AC: 8764 AN: 41476

American (AMR) AF: 0.517 AC: 7899 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.635 AC: 2206 AN: 3472

East Asian (EAS) AF: 0.421 AC: 2175 AN: 5166

South Asian (SAS) AF: 0.595 AC: 2866 AN: 4818

European-Finnish (FIN) AF: 0.606 AC: 6386 AN: 10540

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.535 AC: 36318 AN: 67926

Other (OTH) AF: 0.498 AC: 1051 AN: 2110

Alfa AF: 0.516 Hom.: 38457

Bravo AF: 0.429

Asia WGS AF: 0.527 AC: 1835 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
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.9
DANN	Benign	0.71
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2121743; hg19: chr3-57431985; COSMIC: COSV61056372;