rs34690489

Variant names:

• chr14-102000093-G-A
• rs34690489
• NM_001376.5:c.3909G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-102000093-G-A
• chr14-102000093-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001376.5(DYNC1H1):​c.3909G>A​(p.Ala1303Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,178 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1303A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (95 hom.)
• Consequence: DYNC1H1 NM_001376.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -2.50
• Publications: 9 publications found

Genes affected

DYNC1H1 (HGNC:2961): (dynein cytoplasmic 1 heavy chain 1) Dyneins are a group of microtubule-activated ATPases that function as molecular motors. They are divided into two subgroups of axonemal and cytoplasmic dyneins. The cytoplasmic dyneins function in intracellular motility, including retrograde axonal transport, protein sorting, organelle movement, and spindle dynamics. Molecules of conventional cytoplasmic dynein are comprised of 2 heavy chain polypeptides and a number of intermediate and light chains.This gene encodes a member of the cytoplasmic dynein heavy chain family. [provided by RefSeq, Oct 2008]

DYNC1H1 Gene-Disease associations (from GenCC):

• autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• intellectual disability, autosomal dominant 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• neuronopathy, distal hereditary motor

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease axonal type 2O

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 14-102000093-G-A is Benign according to our data. Variant chr14-102000093-G-A is described in ClinVar as Benign. ClinVar VariationId is 128936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0141 (2150/152292) while in subpopulation AFR AF = 0.0221 (919/41562). AF 95% confidence interval is 0.0209. There are 23 homozygotes in GnomAd4. There are 1022 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2150 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376.5. 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
	DYNC1H1	NM_001376.5	MANE Select	c.3909G>A	p.Ala1303Ala	synonymous	Exon 17 of 78	NP_001367.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	ENST00000360184.10	TSL:1 MANE Select	c.3909G>A	p.Ala1303Ala	synonymous	Exon 17 of 78	ENSP00000348965.4	Q14204
	DYNC1H1	ENST00000681574.1		c.3909G>A	p.Ala1303Ala	synonymous	Exon 17 of 77	ENSP00000505523.1	A0A7P0T9C4
	DYNC1H1	ENST00000679720.1		c.3909G>A	p.Ala1303Ala	synonymous	Exon 17 of 78	ENSP00000505938.1	A0A7P0TA13

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2150 AN: 152174 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.00884 AC: 2224 AN: 251444 AF XY: 0.00840

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00967

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.00987 AC: 14436 AN: 1461886 Hom.: 95 Cov.: 33 AF XY: 0.00953 AC XY: 6932 AN XY: 727244

African (AFR) AF: 0.0229 AC: 768 AN: 33480

American (AMR) AF: 0.0116 AC: 519 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 529 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000742 AC: 64 AN: 86258

European-Finnish (FIN) AF: 0.00197 AC: 105 AN: 53420

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.0105 AC: 11673 AN: 1112006

Other (OTH) AF: 0.0123 AC: 742 AN: 60394

GnomAD4 genome AF: 0.0141 AC: 2150 AN: 152292 Hom.: 23 Cov.: 32 AF XY: 0.0137 AC XY: 1022 AN XY: 74468

African (AFR) AF: 0.0221 AC: 919 AN: 41562

American (AMR) AF: 0.0200 AC: 306 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 751 AN: 68022

Other (OTH) AF: 0.0218 AC: 46 AN: 2110

Alfa AF: 0.0123 Hom.: 13

Bravo AF: 0.0162

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0127

EpiControl AF: 0.0119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Charcot-Marie-Tooth disease axonal type 2O (2)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.0
DANN	Benign	0.61
PhyloP100		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=90/10	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: rs34690489; hg19: chr14-102466430;