chr17-78424004-T-C

Position:

• chr17-78424004-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000262764.11(PGS1):​c.*11-57T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,614,026 control chromosomes in the GnomAD database, including 254 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (223 hom.)
• Consequence: PGS1 ENST00000262764.11 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00800

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002858162).
• BP6: Variant 17-78424004-T-C is Benign according to our data. Variant chr17-78424004-T-C is described in ClinVar as [Benign]. Clinvar id is 1241586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH17	NM_173628.4	c.13291A>G	p.Ile4431Val	missense_variant	81/81	ENST00000389840.7	NP_775899.3
PGS1	NM_024419.5	c.*11-57T>C		intron_variant		ENST00000262764.11	NP_077733.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH17	ENST00000389840.7	c.13291A>G	p.Ile4431Val	missense_variant	81/81	5	NM_173628.4	ENSP00000374490.6
PGS1	ENST00000262764.11	c.*11-57T>C		intron_variant		1	NM_024419.5	ENSP00000262764.5

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 756 AN: 152206 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0966

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0105 AC: 2631 AN: 249740 Hom.: 94 AF XY: 0.00908 AC XY: 1227 AN XY: 135116

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.100

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00359 AC: 5252 AN: 1461702 Hom.: 223 Cov.: 31 AF XY: 0.00343 AC XY: 2494 AN XY: 727134

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0203

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0960

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000729

Gnomad4 OTH exome AF: 0.00500

GnomAD4 genome AF: 0.00494 AC: 753 AN: 152324 Hom.: 31 Cov.: 33 AF XY: 0.00567 AC XY: 422 AN XY: 74486

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0966

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00474 Hom.: 63

Bravo AF: 0.00691

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00925 AC: 1123

Asia WGS AF: 0.0280 AC: 97 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

DNAH17-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.2
DANN	Benign	0.94
DEOGEN2	Benign	0.0039	.;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.53	.;N
REVEL	Benign	0.017
Sift	Benign	0.33	.;T
Vest4		0.11
ClinPred		0.0017	T
GERP RS		0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.13

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: rs78023288; hg19: chr17-76420085; COSMIC: COSV53143127; COSMIC: COSV53143127;