17-78424111-C-T

Position:

• chr17-78424111-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_173628.4(DNAH17):​c.13184G>A​(p.Arg4395Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000104 in 1,613,664 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000086 (1 hom.)
• Consequence: DNAH17 NM_173628.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91

Genes affected

DNAH17 (HGNC:2946): (dynein axonemal heavy chain 17) Dyneins are microtubule-associated motor protein complexes composed of several heavy, light, and intermediate chains. DNAH17 is a heavy chain associated with axonemal dynein (Milisav and Affara, 1998 [PubMed 9545504]).[supplied by OMIM, Mar 2008]

PGS1 (HGNC:30029): (phosphatidylglycerophosphate synthase 1) Predicted to enable CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase activity and calcium ion binding activity. Predicted to be involved in cardiolipin biosynthetic process and diacylglycerol metabolic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

PGS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.054282486).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000282 (43/152334) while in subpopulation EAS AF= 0.000772 (4/5184). AF 95% confidence interval is 0.000498. There are 1 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH17	NM_173628.4	c.13184G>A	p.Arg4395Gln	missense_variant	81/81	ENST00000389840.7	NP_775899.3
PGS1	NM_024419.5	c.*61C>T		3_prime_UTR_variant	10/10	ENST00000262764.11	NP_077733.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH17	ENST00000389840.7	c.13184G>A	p.Arg4395Gln	missense_variant	81/81	5	NM_173628.4	ENSP00000374490.6
PGS1	ENST00000262764.11	c.*61C>T		3_prime_UTR_variant	10/10	1	NM_024419.5	ENSP00000262764.5

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000100 AC: 25 AN: 249410 Hom.: 1 AF XY: 0.0000889 AC XY: 12 AN XY: 134952

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000855 AC: 125 AN: 1461330 Hom.: 1 Cov.: 31 AF XY: 0.0000977 AC XY: 71 AN XY: 726944

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152334 Hom.: 1 Cov.: 33 AF XY: 0.000295 AC XY: 22 AN XY: 74492

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.000291

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2022

The c.13184G>A (p.R4395Q) alteration is located in exon 81 (coding exon 80) of the DNAH17 gene. This alteration results from a G to A substitution at nucleotide position 13184, causing the arginine (R) at amino acid position 4395 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.53	T
REVEL	Benign	0.10
Vest4		0.30
MVP		0.11
ClinPred		0.096	T
GERP RS		4.3
Varity_R		0.080
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs145742397; hg19: chr17-76420192;