rs138940904

Variant names:

• chr3-52395006-G-A
• rs138940904
• NM_015512.5:c.10915G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-52395006-G-A
• chr3-52395006-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015512.5(DNAH1):​c.10915G>A​(p.Ala3639Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,611,868 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.81
• Publications: 5 publications found

Genes affected

DNAH1 (HGNC:2940): (dynein axonemal heavy chain 1) This gene encodes an inner dynein arm heavy chain that provides structural support between the radial spokes and the outer doublet of the sperm tail. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and multiple morphological anomalies of the flagella that result in asthenozoospermia and male infertility. Mice with a homozygous knockout of the orthologous gene are viable but have reduced sperm motility and are infertile. [provided by RefSeq, Feb 2017]

DNAH1 Gene-Disease associations (from GenCC):

• spermatogenic failure 18

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• ciliary dyskinesia, primary, 37

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062885165).
• BP6: Variant 3-52395006-G-A is Benign according to our data. Variant chr3-52395006-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 478392.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00127 (193/152298) while in subpopulation AMR AF = 0.00411 (63/15310). AF 95% confidence interval is 0.0033. There are 1 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015512.5. 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
	DNAH1	NM_015512.5	MANE Select	c.10915G>A	p.Ala3639Thr	missense	Exon 68 of 78	NP_056327.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.10915G>A	p.Ala3639Thr	missense	Exon 68 of 78	ENSP00000401514.2
	DNAH1	ENST00000486752.5	TSL:2	n.11372G>A		non_coding_transcript_exon	Exon 67 of 77
	DNAH1	ENST00000487254.1	TSL:4	n.410G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00129 AC: 315 AN: 244482 AF XY: 0.00133

Gnomad AFR exome AF: 0.000538

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000908

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000752

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.00185

GnomAD4 exome AF: 0.00124 AC: 1812 AN: 1459570 Hom.: 3 Cov.: 32 AF XY: 0.00117 AC XY: 846 AN XY: 725842

African (AFR) AF: 0.000239 AC: 8 AN: 33446

American (AMR) AF: 0.00164 AC: 73 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.000997 AC: 26 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000210 AC: 18 AN: 85692

European-Finnish (FIN) AF: 0.000677 AC: 36 AN: 53192

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00143 AC: 1585 AN: 1110990

Other (OTH) AF: 0.00104 AC: 63 AN: 60296

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74466

African (AFR) AF: 0.000361 AC: 15 AN: 41560

American (AMR) AF: 0.00411 AC: 63 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 68010

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00153 Hom.: 1

Bravo AF: 0.00134

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000965 AC: 4

ESP6500EA AF: 0.00179 AC: 15

ExAC AF: 0.00138 AC: 167

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.87	T
PhyloP100		9.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0080	D
Vest4		0.75
MVP		0.51
MPC		0.56
ClinPred		0.030	T
GERP RS		4.5
gMVP		0.73
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs138940904; hg19: chr3-52429022; COSMIC: COSV101326241; COSMIC: COSV101326241;