6-38848729-C-T

Variant names:

• chr6-38848729-C-T
• rs61748643
• NM_001206927.2:c.5127C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001206927.2(DNAH8):​c.5127C>T​(p.Leu1709Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,612,638 control chromosomes in the GnomAD database, including 204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (18 hom., cov: 32)
  • Exomes 𝑓: 0.011 (186 hom.)
• Consequence: DNAH8 NM_001206927.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.102
• Publications: 4 publications found

Genes affected

DNAH8 (HGNC:2952): (dynein axonemal heavy chain 8) The protein encoded by this gene is a heavy chain of an axonemal dynein involved in sperm and respiratory cilia motility. Axonemal dyneins generate force through hydrolysis of ATP and binding to microtubules. [provided by RefSeq, Jan 2012]

DNAH8 Gene-Disease associations (from GenCC):

• spermatogenic failure 46

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• spermatogenic failure 5

  Inheritance: AR Classification: MODERATE Submitted by: Franklin by Genoox
• primary ciliary dyskinesia

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 6-38848729-C-T is Benign according to our data. Variant chr6-38848729-C-T is described in ClinVar as Benign. ClinVar VariationId is 238651.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.102 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0102 (1554/151928) while in subpopulation SAS AF = 0.0252 (121/4798). AF 95% confidence interval is 0.0216. There are 18 homozygotes in GnomAd4. There are 799 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206927.2. 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
	DNAH8	NM_001206927.2	MANE Select	c.5127C>T	p.Leu1709Leu	synonymous	Exon 37 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.4476C>T	p.Leu1492Leu	synonymous	Exon 36 of 92	NP_001362.2	Q96JB1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.5127C>T	p.Leu1709Leu	synonymous	Exon 37 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.4476C>T	p.Leu1492Leu	synonymous	Exon 35 of 91	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.5127C>T	p.Leu1709Leu	synonymous	Exon 36 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1546 AN: 151810 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00414

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0554

Gnomad EAS AF: 0.0253

Gnomad SAS AF: 0.0250

Gnomad FIN AF: 0.00105

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00887

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0136 AC: 3402 AN: 251016 AF XY: 0.0142

Gnomad AFR exome AF: 0.00431

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.0503

Gnomad EAS exome AF: 0.0243

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00962

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.0115 AC: 16728 AN: 1460710 Hom.: 186 Cov.: 30 AF XY: 0.0118 AC XY: 8609 AN XY: 726698

African (AFR) AF: 0.00383 AC: 128 AN: 33450

American (AMR) AF: 0.0122 AC: 544 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0498 AC: 1301 AN: 26102

East Asian (EAS) AF: 0.0244 AC: 967 AN: 39666

South Asian (SAS) AF: 0.0238 AC: 2050 AN: 86190

European-Finnish (FIN) AF: 0.00199 AC: 106 AN: 53390

Middle Eastern (MID) AF: 0.0154 AC: 89 AN: 5768

European-Non Finnish (NFE) AF: 0.00948 AC: 10538 AN: 1111088

Other (OTH) AF: 0.0167 AC: 1005 AN: 60346

GnomAD4 genome AF: 0.0102 AC: 1554 AN: 151928 Hom.: 18 Cov.: 32 AF XY: 0.0108 AC XY: 799 AN XY: 74230

African (AFR) AF: 0.00422 AC: 175 AN: 41436

American (AMR) AF: 0.0167 AC: 254 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0554 AC: 192 AN: 3468

East Asian (EAS) AF: 0.0252 AC: 130 AN: 5168

South Asian (SAS) AF: 0.0252 AC: 121 AN: 4798

European-Finnish (FIN) AF: 0.00105 AC: 11 AN: 10512

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

European-Non Finnish (NFE) AF: 0.00887 AC: 603 AN: 67984

Other (OTH) AF: 0.0123 AC: 26 AN: 2108

Alfa AF: 0.0118 Hom.: 10

Bravo AF: 0.0103

Asia WGS AF: 0.0280 AC: 97 AN: 3478

EpiCase AF: 0.0115

EpiControl AF: 0.0114

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.15
DANN	Benign	0.59
PhyloP100		-0.10
Mutation Taster		=100/0	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: rs61748643; hg19: chr6-38816505; COSMIC: COSV59433360;