6-38723079-G-C

Variant names:

• chr6-38723079-G-C
• rs180723141
• NM_001206927.2:c.270G>C

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_001206927.2(DNAH8):​c.270G>C​(p.Pro90Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,612,878 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P90P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (20 hom.)
• Consequence: DNAH8 NM_001206927.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.69
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-38723079-G-C is Benign according to our data. Variant chr6-38723079-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00231 (352/152296) while in subpopulation NFE AF = 0.00353 (240/68032). AF 95% confidence interval is 0.00316. There are 1 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 20 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	NM_001206927.2	MANE Select	c.270G>C	p.Pro90Pro	synonymous	Exon 2 of 93	NP_001193856.1
	DNAH8	NM_001371.4		c.-297G>C		5_prime_UTR	Exon 2 of 92	NP_001362.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.270G>C	p.Pro90Pro	synonymous	Exon 2 of 93	ENSP00000333363.7
	DNAH8	ENST00000373278.8	TSL:1	c.270G>C	p.Pro90Pro	synonymous	Exon 2 of 5	ENSP00000362375.4
	DNAH8	ENST00000449981.6	TSL:5	c.270G>C	p.Pro90Pro	synonymous	Exon 1 of 82	ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00275 AC: 671 AN: 243920 AF XY: 0.00281

Gnomad AFR exome AF: 0.000420

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00513

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00378

Gnomad OTH exome AF: 0.00467

GnomAD4 exome AF: 0.00299 AC: 4370 AN: 1460582 Hom.: 20 Cov.: 32 AF XY: 0.00296 AC XY: 2150 AN XY: 726588

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.00288 AC: 129 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00532 AC: 139 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00195 AC: 168 AN: 86258

European-Finnish (FIN) AF: 0.00122 AC: 64 AN: 52284

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.00326 AC: 3620 AN: 1111868

Other (OTH) AF: 0.00341 AC: 206 AN: 60364

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.00223 AC XY: 166 AN XY: 74476

African (AFR) AF: 0.000409 AC: 17 AN: 41568

American (AMR) AF: 0.00294 AC: 45 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00353 AC: 240 AN: 68032

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00293 Hom.: 0

Bravo AF: 0.00251

EpiCase AF: 0.00420

EpiControl AF: 0.00504

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.53
DANN	Benign	0.55
PhyloP100		-1.7
PromoterAI		-0.032	Neutral
Mutation Taster		=100/0	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: rs180723141; hg19: chr6-38690855;